TWI400074B - Condensed heterocyclic derivatives, pharmaceutical compositions containing them and their pharmaceutical use - Google Patents
Condensed heterocyclic derivatives, pharmaceutical compositions containing them and their pharmaceutical use Download PDFInfo
- Publication number
- TWI400074B TWI400074B TW095138520A TW95138520A TWI400074B TW I400074 B TWI400074 B TW I400074B TW 095138520 A TW095138520 A TW 095138520A TW 95138520 A TW95138520 A TW 95138520A TW I400074 B TWI400074 B TW I400074B
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- solvent
- substituent
- hydrate
- ring
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pregnancy & Childbirth (AREA)
- Physical Education & Sports Medicine (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本發明係關於縮合雜環衍生物。This invention relates to condensed heterocyclic derivatives.
更詳言之,本發明係關於具有性腺刺激荷爾蒙釋出荷爾蒙拮抗作用,並可使用於前列腺肥大症、子宮肌瘤、子宮內膜症、子宮纖維腫瘤、青春期早發症、無月經症、月經前症候群、月經困難症等之性荷爾蒙依存性疾病的預防或治療劑等之縮合雜環衍生物,或其前驅藥或其藥理學上所容許之鹽,又或是其水合物或溶媒合物,及含有其之醫藥組成物等。More specifically, the present invention relates to gonad-stimulating hormone releasing hormone antagonism, and can be used for prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroid tumor, early onset of adolescence, no menstrual period, menstruation a condensed heterocyclic derivative such as a prophylactic or therapeutic agent for a sex-related disease such as a pre-existing syndrome or a menstrual disorder, or a prodrug thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof And pharmaceutical compositions containing the same.
性腺刺激荷爾蒙釋出荷爾蒙(Gonadotropin Releasing Hormone:GnRH,或GnRH亦稱為黃體形成荷爾蒙釋出荷爾蒙Luteinizing Hormone Releasing Hormone:LHRH。以下稱為「GnRH」。)係由視丘腦下部所分泌之由10個胺基酸所構成的胜肽(pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2)。由腦下垂體門脈中所分泌之GnRH係經由被認為存在於腦下垂體前葉之受體(GnRH受體)而促進屬於腦下垂體前葉荷爾蒙之性腺刺激荷爾蒙(黃體形成荷爾蒙Luteinizing Hormone:LH、卵細胞刺激荷爾蒙Follicle Stimulating Hormone:FSH)的產生、分泌。此等性腺刺激荷爾蒙作用於性腺(卵巢、精巢)並促進卵細胞之發育、排卵、黃體化和精子形成,同時亦促進性荷爾蒙(動情素、助孕酮、雄性素)的產生、分泌(非專利文獻1)。從而,由於對此GnRH受體具特異性且選擇性的拮抗藥將調節GnRH的作用,並控制性腺刺激荷爾蒙及性荷爾蒙的產生、分泌,故被期待作為性荷爾蒙依存性疾病的預防、治療藥。Gonadotropin Releasing Hormone (GnRH, or GnRH, also known as Luteinizing Hormone Releasing Hormone: LHRH. Hereinafter referred to as "GnRH".) is secreted by the lower part of the hypothalamus. A peptide composed of an amino acid (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2). The GnRH system secreted by the portal vein of the pituitary gland promotes the gonad stimulation hormone belonging to the anterior pituitary hormone through the receptor (GnRH receptor) which is thought to exist in the anterior pituitary gland (the luteal hormone Luteinizing Hormone: LH, Egg cell stimulates the production and secretion of hormone Follicle Stimulating Hormone: FSH. These gonad-stimulating hormones act on the gonads (ovary, testis) and promote the development of egg cells, ovulation, luteinization and sperm formation, and also promote the production and secretion of sex hormones (emotional hormone, progesterone, and male hormone) (non-patented) Document 1). Therefore, since the GnRH receptor-specific and selective antagonist will regulate the action of GnRH and control the production and secretion of hormones and hormones, it is expected to be a preventive and therapeutic drug for sexual hormone-dependent diseases. .
作為抑制GnRH受體功能之藥劑,GnRH受體超促效劑已被使用作為前列腺癌、乳癌及子宮內膜症等之性荷爾蒙依存性疾病的治療藥。GnRH受體超促效劑係結合至GnRH受體,於投予初期呈現過渡性的性腺刺激荷爾蒙分泌刺激作用(急性發作(flareup)現象),其後引起性腺刺激荷爾蒙的枯歇及GnRH受體的機能下降,藉此抑制其功能。從而,GnRH受體超促效劑存在有基於投予初期的性腺刺激荷爾蒙分泌亢進,而病情一時性惡化的問題。另一方面,GnRH受體拮抗藥(以下稱為「GnRH拮抗藥」)之抑制機制為結合阻礙至GnRH受體,故期待不致伴隨性腺刺激荷爾蒙分泌而迅速地表現抑制作用。近年來,開發了Abarelix及Cetrorelix等胜肽性GnRH拮抗藥作為GnRH拮抗藥,並使用於前列腺癌和不孕症等治療上。然而,由於此等胜肽性GnRH拮抗藥屬於難經口吸收性,不得不進行皮下或肌肉內投予,故期待可避免注射部份的局部反應性及具有彈性之用量調節性,並可經口投予之非胜肽性GnRH拮抗藥的開發(參照非專利文獻2)。As a drug that inhibits the function of the GnRH receptor, the GnRH receptor super agonist has been used as a therapeutic drug for a hormone-dependent disease such as prostate cancer, breast cancer, and endometriosis. The GnRH receptor super-agonist binds to the GnRH receptor and exhibits a transitional gonad-stimulating hormone secretion stimulating effect (flareup phenomenon) at the initial stage of administration, which in turn causes gonad-stimulating hormone rush and GnRH receptor The function is reduced, thereby suppressing its function. Therefore, the GnRH receptor super-agonist has a problem that the gonad-stimulated hormone secretion is advanced based on the initial administration, and the condition is temporarily deteriorated. On the other hand, the inhibitory mechanism of the GnRH receptor antagonist (hereinafter referred to as "GnRH antagonist") is that binding to the GnRH receptor is inhibited, so that it is expected that the hormone secretion is not accompanied by the secretion of hormones. In recent years, peptide peptide GnRH antagonists such as Abarelix and Cetrorelix have been developed as GnRH antagonists, and are used for treatments such as prostate cancer and infertility. However, since these peptide GnRH antagonists are difficult to be absorbed by the mouth and have to be administered subcutaneously or intramuscularly, it is expected that the local reactivity and the elasticity of the injection portion can be avoided, and Development of a non-peptide GnRH antagonist for oral administration (see Non-Patent Document 2).
作為具有非胜肽性GnRH拮抗作用之縮合嘧啶衍生物,已知有專利文獻1及2所記載之化合物等。然而,專利文獻1所記載之化合物均為在與嘧啶環縮合之5員環雜環上,具有芳基取代基者。又,專利文獻2所記載之化合物係與芳香族6員環縮合之嘧啶衍生物,經口吸收性必定不高。最近所公開的專利文獻3中,記載有與5員環雜環縮合之具有非胜肽性GnRH拮抗作用的嘧啶衍生物。然而,其對於具有磺醯胺或醯胺基之化合物以外的化合物未有具體記載,再者,對於經口投予時之血中動態亦未有任何具體記載。Examples of the condensed pyrimidine derivatives having a non-peptidic GnRH antagonistic activity include the compounds described in Patent Documents 1 and 2. However, the compounds described in Patent Document 1 are all those having an aryl substituent on a 5-membered ring heterocyclic ring condensed with a pyrimidine ring. Further, the compound described in Patent Document 2 is a pyrimidine derivative which is condensed with an aromatic 6-membered ring, and the oral absorbability is not necessarily high. Patent Document 3 published recently discloses a pyrimidine derivative having a non-peptidic GnRH antagonistic action condensed with a 5-membered ring heterocyclic ring. However, it is not specifically described for compounds other than the compound having a sulfonamide or a guanamine group, and the blood dynamics at the time of oral administration are not specifically described.
作為具有與5員環雜環縮合之嘧啶環的化合物,除了上述之外,可舉例如:專利文獻4中作為絲胺酸蛋白酶抑制劑;專利文獻5中作為血液凝固第Xa因子抑制劑;專利文獻6中作為除草劑等各種化合物。然而,此等文獻中,對於本發明之具有與5員環雜環縮合之嘧啶環的化合物係具有GnRH拮抗作用之情事,並未有記載或教示。Examples of the compound having a pyrimidine ring condensed with a 5-membered ring heterocyclic ring include, for example, Patent Document 4 as a serine protease inhibitor; Patent Document 5 as a blood coagulation factor Xa inhibitor; In Document 6, various compounds such as herbicides are used. However, in these documents, the compound having a pyrimidine ring condensed with a 5-membered ring heterocyclic ring of the present invention has a GnRH antagonistic action and is not described or taught.
非專利文獻1:「標準生理學」、第5版、醫學書院、pp.882-891非專利文獻2:「產科與婦人科」、2004年、第71卷、3號、pp.280-285、301-307Non-Patent Document 1: "Standard Physiology", Fifth Edition, Medical College, pp. 882-891 Non-Patent Document 2: "Obstetrics and Women's Division", 2004, Vol. 71, No. 3, pp. 280-285 301-307
專利文獻1:國際公開第1996/24597號說明冊專利文獻2:國際公開第2005/019188號說明冊專利文獻3:國際公開第2006/083005號說明冊專利文獻4:美國專利申請公開第2003/0004167號說明書專利文獻5:國際公開第00/39131號說明冊專利文獻6:日本專利特表平6-510992號公報Patent Document 1: International Publication No. 1996/24597 Annotated Patent Document 2: International Publication No. 2005/019188 Annotated Patent Document 3: International Publication No. 2006/083005 Annotated Patent Document 4: US Patent Application Publication No. 2003/ Patent Document No. 0004167 Patent Document 5: International Publication No. 00/39131 Annotated Patent Document 6: Japanese Patent Laid-Open No. Hei 6-510992
本發明之課題在於提供具有GnRH拮抗作用之化合物。An object of the present invention is to provide a compound having GnRH antagonistic action.
本發明者等人為解決上述課題而潛心研究,結果首次發現,以下述一般式(I)所示之與5員環雜環縮合之嘧啶衍生物係具有優越的GnRH拮抗作用,相較於與芳香族6員環縮合之嘧啶衍生物,於經口投予方面顯示優良的血中動態,遂完成本發明。The inventors of the present invention have intensively studied to solve the above problems, and as a result, it has been found for the first time that a pyrimidine derivative condensed with a 5-membered ring heterocyclic ring represented by the following general formula (I) has superior GnRH antagonistic action, compared with aroma. The 6-membered ring-condensed pyrimidine derivative exhibits excellent blood dynamics in oral administration, and the present invention has been completed.
亦即,本發明係關於[1]一種縮合雜環衍生物或其前驅藥或其藥理學上所容許之鹽或其之水合物或溶媒合物,係以一般式(I)所示:
本發明之縮合雜環衍生物(I)或其前驅藥或其藥理學上所容許之鹽或其之水合物或溶媒合物,由於具有優越的GnRH拮抗作用,故可調節性腺刺激荷爾蒙釋出荷爾蒙的作用,控制性腺刺激荷爾蒙及性荷爾蒙的產生、分泌,藉此而使用作為性荷爾蒙依存性疾病的預防或治療劑。The condensed heterocyclic derivative (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof thereof, can regulate gonadotropin-stimulated hormone release due to superior GnRH antagonism The role of hormones to control the production and secretion of hormones and sex hormones, thereby using as a preventive or therapeutic agent for sexual hormone-dependent diseases.
本說明書中之用語意義係如下述。The meanings of the terms used in this specification are as follows.
「5員環不飽和烴」係指具有1個或2個雙鍵之5員環的烴環。The "5-membered ring unsaturated hydrocarbon" means a hydrocarbon ring having a 5-membered ring of one or two double bonds.
「雜芳基」係指具有1個或2個以上之由氮原子、氧原子及硫原子任意選擇之雜原子的單環式雜芳基(例如噻唑、唑、異噻唑、異唑、吡啶、嘧啶、吡、嗒、吡咯、呋喃、噻吩、咪唑、吡唑、二唑、噻二唑、三唑、四唑、呋呫等)。"Heteroaryl" means a monocyclic heteroaryl group having one or more hetero atoms selected arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom (for example, thiazole, Oxazole, isothiazole, iso Oxazole, pyridine, pyrimidine, pyridyl ,despair , pyrrole, furan, thiophene, imidazole, pyrazole, Diazole, thiadiazole, triazole, tetrazole, furazan, etc.).
「可取代」係指亦可具有取代基。"Substitutable" means that it may have a substituent.
「5員環雜芳基」係指5員單環之上述雜芳基,可舉例如噻唑、唑、異噻唑、異唑、吡咯、呋喃、噻吩、咪唑、吡唑、二唑、噻二唑、三唑、呋呫環。"5-membered ring heteroaryl" means a heterocyclic group of the above 5-membered monocyclic ring, and examples thereof include thiazole, Oxazole, isothiazole, iso Oxazole, pyrrole, furan, thiophene, imidazole, pyrazole, Diazole, thiadiazole, triazole, furoxan ring.
「芳基」係指苯基。"Aryl" means phenyl.
「鹵原子」係指氟原子、氯原子、溴原子或碘原子。The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
「低級烷基」係指甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、第三戊基、己基等之碳數1~6之亦可分枝的烷基。"Lower alkyl" means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, pentyl, isopentyl, neopentyl, third A pentyl group, a hexyl group or the like having a carbon number of 1 to 6 which may also be branched.
「低級烯基」係指乙烯基、烯丙基、1-丙烯基、異丙烯基、1-丁烯基、2-丁烯基、2-甲基烯丙基等之碳數2~6之亦可分枝的烯基。"Lower alkenyl" means a carbon number of 2 to 6 such as a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group or a 2-methylallyl group. Alkenyl groups can also be branched.
「低級炔基」係指乙炔基、2-丙炔基等之碳數2~6之亦可分枝的炔基。The "lower alkynyl group" means an alkynyl group having a carbon number of 2 to 6 which may be branched, such as an ethynyl group or a 2-propynyl group.
「低級烷基磺醯基」係指以上述低級烷基予以取代的磺醯基。The "lower alkylsulfonyl group" means a sulfonyl group substituted with the above lower alkyl group.
「低級烷基亞磺醯基」係指以上述低級烷基予以取代的亞磺醯基。The "lower alkyl sulfinyl group" means a sulfinyl group substituted with the above lower alkyl group.
「低級伸烷基」係指碳數1~6之亦可分枝的伸烷基。"Lower alkylene" means an alkylene group having a carbon number of 1 to 6 which may also be branched.
「C1 - 3 伸烷基」係指碳數1~3之亦可分枝的伸烷基。"C 1 - 3 alkylene group" means a carbon number may also be branched alkylene of 1 to 3.
「低級烷氧基」係指甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、第二丁氧基、第三丁氧基、戊氧基、異戊氧基、新戊氧基、第三戊氧基、己氧基等之碳數1~6之亦可分枝的烷氧基。"Lower alkoxy" is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, tert-butoxy, pentyloxy, iso Alkoxy groups having a carbon number of 1 to 6 which may be branched by a pentyloxy group, a neopentyloxy group, a third pentyloxy group, a hexyloxy group or the like.
「低級烷氧基羰基」係指碳數2~7之亦可分枝的烷氧基羰基。"Lower alkoxycarbonyl" means an alkoxycarbonyl group having a carbon number of 2 to 7 which may also be branched.
「低級烷基硫」係指碳數1~6之亦可分枝的烷基硫。"Lower alkyl sulphide" means an alkyl sulphide having a carbon number of 1 to 6 which may also be branched.
「環烷基」係指碳數3~8之單環式環烷基(例如環丙基、環丁基、環戊基、環己基、環庚基、環啈基等之單環式環烷基)。"Cycloalkyl" means a monocyclic cycloalkyl group having 3 to 8 carbon atoms (for example, a monocyclic naphthenic group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclodecyl group). base).
「雜環烷基」係指具有1個或2個以上之由氮原子、氧原子及硫原子任意選擇之雜原子,並亦可具有1~2個側氧基之3~8員環雜環烷基(例如:吡咯啶基、哌啶基、側氧哌啶基、啉基、哌基、側氧哌基、噻啉基、呯基(azepanyl)、二呯基、呯基(oxazepanyl)、噻呯基(thiazepanyl)、二側氧噻呯基、偶氮啃基(azocanyl)、四氫呋喃基、四氫吡喃基等),於環內具有硫原子的情況下,該硫原子亦可被氧化。"Heterocycloalkyl" means a 3-8 membered ring heterocyclic ring having one or two or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 1 to 2 pendant oxy groups. Alkyl (eg pyrrolidinyl, piperidinyl, oxoperipyryl, Olinyl group, piperazine Oxyporide Base Alkyl group, azepanyl, dimercapto group, An oxazepanyl, thiazepanyl, acesulfame group, azocanyl, tetrahydrofuranyl, tetrahydropyranyl group, etc., in the case where a sulfur atom is present in the ring, Sulfur atoms can also be oxidized.
「亦可縮環」係指亦可與由上述環烷基、上述雜環烷基、上述芳基及上述雜芳基選擇之1個環進行縮合。作為「經縮環之環烷基」、「經縮環之雜環烷基」、「經縮環之芳基」及「經縮環之雜芳基」,可舉例如吲哚基、異吲哚基、苯并呋喃基、異苯并呋喃基、苯并噻吩基、苯并唑基、苯并噻唑基、苯并異唑基、苯并異噻唑基、吲唑基(Indazolyl)、苯并咪唑基、喹啉基、異喹啉基、酞基(Phthalazinyl)、喹啉基、喹唑啉基、啉基(Cinnolinyl)、吲基(Indolizinyl)、萘啶基(Naphthyridinyl)、喋啶基(Pteridinyl)、茚(Indanyl)、萘基、1,2,3,4-四氫萘基、吲哚啉基、異吲哚啉基、2,3,4,5-四氫苯并[b]呯基(oxepinyl)、6,7,8,9-四氫-5H-苯并環庚烯基、基(chromanyl)等,鍵結手(valency)可由任一環付出。The "condensable ring" means that it may be condensed with one ring selected from the above cycloalkyl group, the above heterocycloalkyl group, the above aryl group, and the above heteroaryl group. Examples of the "cycloalkyl group which is condensed ring", "heterocycloalkyl group which is condensed ring", "aryl group which is condensed ring", and "heteroaryl group which is condensed ring" include, for example, fluorenyl group and isoindole. Mercapto, benzofuranyl, isobenzofuranyl, benzothienyl, benzo Azolyl, benzothiazolyl, benzopyrene Azyl, benzisothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, anthracene Phthalazinyl, quin Lolinyl, quinazolinyl, Cinnolinyl, 吲 Indolizinyl, Naphthyridinyl, Pteridinyl, Indanyl, Naphthyl, 1,2,3,4-tetrahydronaphthyl, porphyrin, Isoporphyrin , 2,3,4,5-tetrahydrobenzo[b] Oxepinyl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, For chromanyl, etc., valency can be paid by either ring.
「環狀胺基」係指上述亦可縮環之雜環烷基中,於環內具有鍵結部位之具有至少1個氮原子的基,可舉例如:1-吡咯啶基、1-哌啶基、1-哌基、4-啉基、4-噻啉基、2,3,4,5,6,7-六氫-1H-呯-1-基、1-吲哚啉基、2-異吲哚啉基、3,4-二氫-1,5-萘啶-1(2H)-基、1,2,3,4-四氫喹啉-1-基、3,4-二氫喹啉-1(2H)-基、3,4-二氫異喹啉-2(1H)-基、八氫喹啉-1(2H)-基、八氫異喹啉-2(1H)-基、過氫喹啉、2,3-二氫-4H-1,4-苯并-4-基、2,3-二氫-4H-1,4-苯并噻-4-基、3,4-二氫喹啉-1(2H)-基、2,3-二氫-4H-吡哆[3,2-b][1,4]-4-基、2,3,4,5,-四氫-1H-1-苯并呯-1-基、1,3,4,5-四氫-2H-2-苯并呯-2-基、3,4-二氫-1,5-苯并呯-5(2H)-基、2,3-二氫-4,1-苯并噻呯-1(5H)-基、3,4-二氫-1,5-苯并噻呯-5(2H)-基、2,3-二氫-4,1-苯并噻呯-1(5H)-基、2,3,4,5-四氫-1H-1,5-苯并二呯-1-基、2,3,4,5-四氫-1H-1,4-苯并二呯-1-基、5,6,7,8-四氫-4H-噻吩[3,2-b]呯-4-基、3,4,5,6-四氫-1-苯并唑-1(2H)-基等。The "cyclic amine group" means a group having at least one nitrogen atom in a heterocyclic alkyl group which may also be condensed, and having a bonding site in the ring, and examples thereof include a 1-pyrrolidinyl group and a 1-piperidyl group. Pyridyl, 1-piper Base, 4- Olinyl, 4-thia Boryl, 2,3,4,5,6,7-hexahydro-1H-indol-1-yl, 1-carbolinyl, 2-isoindolyl, 3,4-dihydro-1, 5-naphthyridin-1(2H)-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 3,4-dihydroquinolin-1(2H)-yl, 3,4-di Hydrogen isoquinoline-2(1H)-yl, octahydroquinoline-1(2H)-yl, octahydroisoquinoline-2(1H)-yl, perhydroquinoline, 2,3-dihydro-4H -1,4-Benzene 4-yl, 2,3-dihydro-4H-1,4-benzothiazide 4-yl, 3,4-dihydroquine Porphyrin-1(2H)-yl, 2,3-dihydro-4H-pyridinium [3,2-b][1,4] 4-yl, 2,3,4,5,-tetrahydro-1H-1-benzoindole-1-yl, 1,3,4,5-tetrahydro-2H-2-benzoindole-2- Base, 3,4-dihydro-1,5-benzo Indole-5(2H)-yl, 2,3-dihydro-4,1-benzothiazepin-1(5H)-yl, 3,4-dihydro-1,5-benzothiazepine-5 ( 2H)-yl, 2,3-dihydro-4,1-benzothiazepine-1(5H)-yl, 2,3,4,5-tetrahydro-1H-1,5-benzodioxan- 1-yl, 2,3,4,5-tetrahydro-1H-1,4-benzodioxin-1-yl, 5,6,7,8-tetrahydro-4H-thiophene [3,2-b呯-4-yl, 3,4,5,6-tetrahydro-1-benzoxazole -1 (2H)-yl group and the like.
「(二)低級烷基胺基」係指以上述低級烷基經單或二取代之胺基,二取代之2個低級烷基可為不同,2個低級烷基亦可與兩者所結合鄰接之氮原子一同形成環狀胺基。"(2) Lower alkylamino group" means an amine group which is mono- or disubstituted with the above lower alkyl group, and the two lower alkyl groups which are disubstituted may be different, and the two lower alkyl groups may be combined with the two. Adjacent nitrogen atoms together form a cyclic amine group.
「(二)低級烷基胺甲醯基」係指以上述低級烷基經單或二取代之胺甲醯基,二取代之2個低級烷基可為不同,2個低級烷基亦可與兩者所結合鄰接之氮原子一同形成環狀胺基。"(2) Lower alkylamine-methyl indenyl" means an aminomethyl group which is mono- or disubstituted with the above lower alkyl group, and the two lower alkyl groups which are disubstituted may be different, and two lower alkyl groups may also be used. The nitrogen atoms adjacent to the two together form a cyclic amine group.
「醯基」係指碳數2~7之亦可分枝的脂肪族羧酸醯基、環烷基羧酸醯基、雜環烷基羧酸醯基、芳基羧酸醯基、雜芳基羧酸醯基。"醯基" means an aliphatic carboxylic acid fluorenyl group, a cycloalkyl carboxylic acid fluorenyl group, a heterocycloalkyl carboxylic acid fluorenyl group, an aryl carboxylic acid fluorenyl group, a heteroaryl group having a carbon number of 2 to 7. A carboxylic acid thiol group.
「醯基胺基」係指以上述醯基予以取代之胺基。"Nylideneamino group" means an amine group substituted with the above fluorenyl group.
一般式(I)中,環A較佳為5員環雜芳基,更佳為噻吩基,特佳為以下式所示之噻吩環。In the general formula (I), the ring A is preferably a 5-membered ring heteroaryl group, more preferably a thienyl group, and particularly preferably a thiophene ring represented by the following formula.
一般式(I)中,作為E1 ,較佳為氧原子。作為E2 ,以氧原子為佳。In the general formula (I), as E 1 , an oxygen atom is preferred. As E 2 , an oxygen atom is preferred.
一般式(I)中,作為環B,較佳為苯環、噻吩環或吡啶環,更佳為苯環或噻吩環。此情況下,環B的鍵結位置較佳為下式所示者:
特佳為下式所示者:
於n為1或2的情況,環上具有RB
的環B較佳為以下式:
一般式(I)中,U較佳為單鍵、亞甲基或伸乙基。In the general formula (I), U is preferably a single bond, a methylene group or an extended ethyl group.
特別是於下述各種情況下時,其血中動態良好,而為較佳:(i)於U為單鍵的情況,作為X係-S-L-Y、-O-L-Y、-CO-L-Y、或-SO2 -L-Y所示之基(式中,L為可取代低級伸烷基;Y為Z或-NW7 W8 〔W7 及W8 獨立為氫原子、可取代低級烷基或Z(但不同時為氫原子),或W7 及W8 亦可與兩者所結合鄰接之氮原子一同形成可取代環狀胺基〕所示之基;Z為亦可縮環之可取代環烷基、亦可縮環之可取代雜環烷基、亦可縮環之可取代芳基、或亦可縮環之可取代雜芳基);(ii)於U為亞甲基的情況,作為X係-Y(其中,Y為-NW7 W8 〔W7 及W8 獨立為氫原子、可取代低級烷基或Z(但不同時為氫原子,W7 較佳為Z),或W7 及W8 亦可與兩者所結合鄰接之氮原子一同形成可取代環狀胺基〕)、-S-Z或-O-Z所示之基;(iii)於U為伸乙基的情況,X係-Y(其中,Y為Z,Z與上述同義)。In particular, in the following various cases, the blood dynamics are good, and it is preferable: (i) in the case where U is a single bond, as X-s-L-Y, -O-L-Y, - a group represented by CO-L-Y or -SO 2 -L-Y (wherein L is a substitutable lower alkyl group; Y is Z or -NW 7 W 8 [W 7 and W 8 are independently hydrogen atoms) And may be substituted for lower alkyl or Z (but not hydrogen atom at the same time), or W 7 and W 8 may form a group substituted with a cyclic amino group together with a nitrogen atom adjacent to the two; Z is a condensed ring which may be substituted with a cycloalkyl group, a condensed ring which may be substituted with a heterocycloalkyl group, a condensed ring which may be substituted with an aryl group, or a condensed ring which may be substituted with a heteroaryl group; (ii) In the case where U is a methylene group, X is a Y-form (wherein Y is -NW 7 W 8 [W 7 and W 8 are independently a hydrogen atom, a lower alkyl group or a Z (but not a hydrogen atom at the same time, W) 7 is preferably Z), or W 7 and W 8 may be combined with a nitrogen atom adjacent to the two to form a group which may be substituted with a cyclic amine group]), -S-Z or -O-Z; Iii) In the case where U is an ethyl group, X is -Y (wherein Y is Z, Z is synonymous with the above).
作為L,更佳為C1 - 3 低級伸烷基。As L, a C 1 - 3 lower alkylene group is more preferable.
作為Z,較佳為亦可縮環之可取代雜芳基或亦可縮環之可取代芳基,更佳為亦可縮環之可取代芳基。Z之中,作為可取代雜芳基或可取代芳基所亦可具有的取代基,較佳為鹵原子、可取代低級烷基、或可取代低級烷氧基,更佳為鹵原子、亦可以鹵原子或低級烷氧基或羥基予以取代之低級烷基、或亦可以鹵原子或低級烷氧基或羥基予以取代之低級烷氧基。As Z, a substitutable heteroaryl group which may also be a condensed ring or a substitutable aryl group which may also be a condensed ring is preferred, and a substituted aryl group which may also be a condensed ring is more preferred. Among Z, a substituent which may be possessed as a substitutable heteroaryl group or a substitutable aryl group is preferably a halogen atom, a substitutable lower alkyl group, or a substitutable lower alkoxy group, more preferably a halogen atom. A lower alkyl group which may be substituted with a halogen atom or a lower alkoxy group or a hydroxyl group, or a lower alkoxy group which may be substituted with a halogen atom or a lower alkoxy group or a hydroxyl group.
作為可取代環狀胺基、可取代環烷基或可取代雜環烷基所亦可具有的取代基,可舉例如側氧基、鹵原子、氰基、氫氧基、可取代低級烷基、環烷基、可取代低級烷氧基、可取代低級烷硫基、羧基、可取代低級烷氧基羧基、胺甲醯基、(二)低級烷氧基胺甲醯基、可取代芳基、芳基氧基、雜芳基、雜芳基氧基、醯基胺基等,此等基可為相同或不同的複數取代。其中,RA 中,作為NW2 W3 所形成之可取代環狀胺基所亦可具有的取代基,係排除含芳基之基。Examples of the substituent which may be substituted with a cyclic amino group, a substituted cycloalkyl group or a substituted heterocycloalkyl group include a pendant oxy group, a halogen atom, a cyano group, a hydroxyl group, and a substitutable lower alkyl group. , cycloalkyl, substitutable lower alkoxy, substitutable lower alkylthio, carboxy, substitutable lower alkoxycarboxy, amine mercapto, (b) lower alkoxyamine, mercapto, substituted aryl , aryloxy, heteroaryl, heteroaryloxy, decylamino, and the like, which may be the same or different complex substitutions. Among them, in R A , a substituent which may be possessed as a substitutable cyclic amino group formed by NW 2 W 3 excludes an aryl group-containing group.
作為可取代芳基或可取代雜芳基所亦可具有的取代基,可舉例如鹵原子、硝基、氰基、羥基、可取代低級烷基、環烷基、可取代低級烷氧基、可取代低級烷硫基、羧基、可取代低級烷氧基羧基、胺甲醯基、(二)低級烷基胺甲醯基、芳基、芳基氧基、雜芳基、雜芳基氧基、醯基胺基等,此等基亦可為相同或不同的複數取代。Examples of the substituent which the substitutable aryl group or the substituted heteroaryl group may have include a halogen atom, a nitro group, a cyano group, a hydroxyl group, a substitutable lower alkyl group, a cycloalkyl group, a substitutable lower alkoxy group, and the like. Substitutable lower alkylthio, carboxy, substitutable lower alkoxycarboxy, amine mercapto, (b) lower alkylamine, aryl, aryloxy, heteroaryl, heteroaryloxy And mercaptoamine groups, etc., these groups may also be substituted by the same or different complex numbers.
於亦可縮環之可取代環烷基、亦可縮環之可取代雜環烷基、亦可縮環之可取代芳基、及亦可縮環之可取代雜芳基中,上述取代基亦可取代為進行縮環之相同或不同的複數環。The above substituent may be substituted with a cycloalkyl group, a condensed ring-substituted heterocycloalkyl group, a condensed ring-substituted aryl group, and a condensed ring-substituted heteroaryl group. It may also be replaced by the same or different complex rings of the condensed ring.
於Z為亦可縮環之可取代環烷基或亦可縮環之可取代雜環烷基的情況,作為該等基所亦可具有的取代基,較佳為可取代芳基或雜芳基。In the case where Z is a substitutable cycloalkyl group which may also be condensed or may be substituted with a heterocycloalkyl group, the substituent which may be possessed as such a group is preferably a substitutable aryl group or a heteroaryl group. base.
作為可取代低級烷基、可取代低級伸烷基、可取代低級烯基、可取代低級炔基、可取代低級烷基磺醯基、可取代低級烷基亞磺醯基、可取代低級烷氧基、可取代低級烷硫基、或可取代低級烷氧基羰基所亦可具有的取代基,可舉例如鹵原子、氰基、羥基、低級烷氧基、低級烷硫基、胺基、(二)低級烷基胺基、羧基、低級烷氧基羰基、胺甲醯基、(二)低級烷基胺甲醯基、芳基、雜芳基等,此等基亦可為相同或不同之複數取代。其中,RA 中,係排除含芳基之基及含雜芳基之基。As a substitutable lower alkyl group, a substitutable lower alkyl group, a substitutable lower alkenyl group, a substitutable lower alkynyl group, a substitutable lower alkyl sulfonyl group, a substitutable lower alkyl sulfinyl group, a substitutable lower alkoxy group The substituent which may be substituted by a lower alkylthio group or a lower alkoxycarbonyl group may, for example, be a halogen atom, a cyano group, a hydroxyl group, a lower alkoxy group, a lower alkylthio group or an amine group, a) a lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, an amine carbenyl group, a (di) lower alkylamine formamyl group, an aryl group, a heteroaryl group, etc., and these groups may be the same or different Multiple substitution. Wherein, in R A , an aryl group-containing group and a heteroaryl group-containing group are excluded.
以下表示本發明中一般式(I)所示之縮合雜環衍生物的製造方法之一例。An example of a method for producing a condensed heterocyclic derivative represented by the general formula (I) in the present invention is shown below.
本發明之一般式(I)所示之縮合雜環衍生物中,E1 為氧原子之化合物,係可依例如製法1之方法予以製造。In the condensed heterocyclic derivative represented by the general formula (I) of the present invention, a compound wherein E 1 is an oxygen atom can be produced, for example, by the method of Process 1.
式中之R1 為硝基或低級烷氧羰基,環A、環B、RA 、RB 、m、n、E2 、U、X係與上述同義。Wherein R 1 is a nitro group or a lower alkoxycarbonyl group, and ring A, ring B, R A , R B , m, n, E 2 , U, and X are synonymous with the above.
(步驟1-1)於惰性溶媒(例如四氫呋喃、二氯甲烷、其等之混合溶媒等)中,使用光氣、二光氣、三光氣等試劑,於鹼(例如三乙基胺、N,N-二異丙基乙基胺、吡啶等)存在下,使胺化合物(1 )於一般為冰冷~迴流溫度下,處理30分鐘~1天,藉此可轉換為異氰酸酯化合物(2 )。(Step 1-1) In an inert solvent (for example, tetrahydrofuran, dichloromethane, a mixed solvent thereof, etc.), a reagent such as phosgene, diphosgene or triphosgene is used in a base (for example, triethylamine, N, In the presence of N-diisopropylethylamine, pyridine, etc., the amine compound ( 1 ) can be converted to the isocyanate compound ( 2 ) by treatment at a temperature of from ice-cold to reflux for 30 minutes to 1 day.
(步驟1-2)於惰性溶媒(例如四氫呋喃、二氯甲烷等)中,於鹼(例如三乙基胺、N,N-二異丙基乙基胺、吡啶、4-二甲基胺基吡啶等)存在下或非存在下,使異氰酸酯化合物(2 )與胺化合物(3 )於一般為冰冷~迴流溫度下,反應1小時~3天,藉此可製造脲化合物(4 )或本發明之縮合雜環衍生物(Ia)。(Step 1-2) in an inert solvent (e.g., tetrahydrofuran, dichloromethane, etc.) in a base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylamino) The isocyanate compound ( 2 ) and the amine compound ( 3 ) are reacted in an ice-cold-reflux temperature for 1 hour to 3 days in the presence or absence of pyridine, etc., whereby the urea compound ( 4 ) or the present invention can be produced. A condensed heterocyclic derivative (Ia).
(步驟1-3)於惰性溶媒(例如四氫呋喃、二氯甲烷、甲醇、乙醇、N,N-二甲基甲醯胺、水等)中,於鹼(例如三乙基胺、N,N-二異丙基乙基胺、吡啶、4-二甲基胺基吡啶、甲氧鈉、乙氧鈉、氫化鈉、氫氧化鈉等)存在下或非存在下,使脲化合物(4 )於一般為冰冷~迴流溫度下,反應5分鐘~3天,藉此可製造本發明之縮合雜環衍生物(Ia)。(Step 1-3) in an inert solvent (e.g., tetrahydrofuran, dichloromethane, methanol, ethanol, N,N-dimethylformamide, water, etc.) in a base (e.g., triethylamine, N, N-) Urea compound ( 4 ) in the presence or absence of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium hydride, sodium hydroxide, etc. The condensed heterocyclic derivative (Ia) of the present invention can be produced by reacting for 5 minutes to 3 days under ice-cold temperature.
本發明之一般式(I)所示之縮合雜環衍生物中,E2 為氧原子之化合物,係可依例如製法2之方法予以製造。In the condensed heterocyclic derivative represented by the general formula (I) of the present invention, a compound wherein E 2 is an oxygen atom can be produced, for example, by the method of Process 2.
式中之環A、環B、RA 、RB 、m、n、U、X係與上述同義。Ring A, ring B, R A , R B , m, n, U, and X in the formula are synonymous with the above.
(步驟2-1)將羧酸化合物(5 )與胺化合物(3 ),藉由一般之氯化酸法或縮合劑法所進行之縮合,則可製造醯胺化合物(6 )。氯化酸法係可例如於惰性溶媒(二氯甲烷、1,2-二氯乙烷、甲苯)中,使用亞硫醯氯、草醯氯等試劑,於添加劑(例如N,N-二甲基甲醯胺等)存在下或非存在下,使羧酸化合物(5 )於一般為冰冷~迴流溫度下,處理30分鐘~1天,藉此作成為氯化酸後,於惰性溶媒(例如吡啶、二氯甲烷、四氫呋喃、水等)中,於鹼(三乙基胺、N,N-二異丙基乙基胺、吡啶、4-二甲基胺基吡啶、碳酸鉀、碳酸氫鈉等)存在下或非存在下,與胺化合物(3 )於一般為冰冷~迴流溫度下,反應1小時~3天。縮合劑法係可例如於惰性溶媒(N,N-二甲基甲醯胺、二氯甲烷、四氫呋喃)中,使用縮合劑(1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺鹽酸鹽、二環己基碳二醯亞胺等),於添加劑(1-羥基苯并三唑等)存在下,於鹼(三乙基胺、N,N-二異丙基乙基胺、吡啶、4-二甲基胺基吡啶等)存在下或非存在下,使羧酸化合物(5 )與胺化合物(3 )於一般為室溫~迴流溫度下,反應1小時~3天。(Step 2-1) The guanamine compound ( 6 ) can be produced by condensing the carboxylic acid compound ( 5 ) with the amine compound ( 3 ) by a general chlorination method or a condensing agent method. The chlorinated acid method can be used, for example, in an inert solvent (dichloromethane, 1,2-dichloroethane, toluene), using a reagent such as sulfinium chloride or oxalic acid chloride in an additive such as N, N-dimethyl The carboxylic acid compound ( 5 ) is treated in an ice-cold-reflux temperature for 30 minutes to 1 day in the presence or absence of a carbamide or the like, thereby being used as a chlorinated acid in an inert solvent (for example, In pyridine, dichloromethane, tetrahydrofuran, water, etc., in a base (triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydrogencarbonate In the presence or absence of the amine compound ( 3 ), it is reacted for 1 hour to 3 days at a temperature of usually cold-reflux. The condensing agent system can be used, for example, in an inert solvent (N,N-dimethylformamide, dichloromethane, tetrahydrofuran) using a condensing agent (1-ethyl-3-(3-dimethylaminopropyl) ) carbodiimide hydrochloride, dicyclohexylcarbodiimide, etc. in the presence of an additive (1-hydroxybenzotriazole, etc.) in a base (triethylamine, N, N-diiso) In the presence or absence of propylethylamine, pyridine, 4-dimethylaminopyridine, etc., the carboxylic acid compound ( 5 ) and the amine compound ( 3 ) are reacted at room temperature to reflux temperature. Hours ~ 3 days.
(步驟2-2)將胺化合物(6 )之硝基,藉由一般之接觸還原法或金屬氫錯合物還原法等所進行之還原,則可製造胺化合物(7 )。接觸還原法係可例如於惰性溶媒(甲醇、乙醇、醋酸乙酯、四氫呋喃、醋酸等)中,使用觸媒(鈀碳粉末等),使醯胺化合物(6 )於一般為室溫~迴流溫度下,處理1小時~3天。金屬氫錯合物還原法係可例如於惰性溶媒(甲醇、乙醇、四氫呋喃等)中,使用還原劑(氫化硼鈉等),於添加劑(溴化鎳(II)等)存在下,使醯胺化合物(6 )於一般為冰冷~室溫下,處理30分鐘~1天。(Step 2-2) The nitro amine compound (6), the contacting being carried out by the general reduction method of reducing a metal hydrogen complex compound or a reduction method, etc. can be manufactured amine compound (7). The contact reduction method can be carried out, for example, in an inert solvent (methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, etc.) using a catalyst (palladium carbon powder or the like) to cause the guanamine compound ( 6 ) to be generally at room temperature to reflux. At temperature, treat for 1 hour to 3 days. The metal hydrogen complex reduction method can be used, for example, in an inert solvent (methanol, ethanol, tetrahydrofuran, etc.) using a reducing agent (sodium borohydride or the like) in the presence of an additive (nickel (II) bromide or the like) to give a guanamine. Compound ( 6 ) is treated for 30 minutes to 1 day at room temperature generally at room temperature.
(步驟2-3)於惰性溶媒(例如四氫呋喃、二氯甲烷、N,N-二甲基甲醯胺等)中,使用光氣、二光氣、三光氣、1,1’-羰基雙-1H-咪唑等試劑,於鹼(例如三乙基胺、N,N-二異丙基乙基胺、吡啶、4-二甲基胺基吡啶、氫化鈉等)存在下或非存在下,使胺化合物(7 )於一般為冰冷~迴流溫度下,處理30分鐘~1天,藉此可製造本發明之縮合雜環衍生物(Ib)。(Step 2-3) In an inert solvent (for example, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, etc.), phosgene, diphosgene, triphosgene, 1,1'-carbonyldi- a reagent such as 1H-imidazole, in the presence or absence of a base (for example, triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydride, etc.), The amine compound ( 7 ) is treated at a temperature of from ice-cold to reflux for 30 minutes to 1 day, whereby the condensed heterocyclic derivative (Ib) of the present invention can be produced.
(步驟2-4)於惰性溶媒(四氫呋喃、N,N-二甲基甲醯胺、甲醇、乙醇)中,使用二硫化碳等試劑,於鹼(三乙基胺、N,N-二異丙基乙基胺、氫化鈉、氫氧化鈉、氫氧化鉀等)存在下,使胺化合物(7 )於一般為冰冷~迴流溫度下,處理1小時~3天,藉此可製造本發明之縮合雜環衍生物(Ic)。(Step 2-4) In an inert solvent (tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol), using a reagent such as carbon disulfide in a base (triethylamine, N,N-diisopropyl In the presence of ethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, etc., the amine compound ( 7 ) is treated at a temperature of from ice-cold to reflux for 1 hour to 3 days, whereby the condensed impurities of the present invention can be produced. Ring derivative (Ic).
(步驟2-5)於惰性溶媒(四氫呋喃、N,N-二甲基甲醯胺、甲醇、乙醇等)中,使用二苯基氰基碳醯亞胺酯(carbonimidate)等試劑,於鹼(三乙基胺、N,N-二異丙基乙基胺、氫化鈉、氫氧化鈉、氫氧化鉀等)存在下,使胺化合物(7 )於一般為冰冷~迴流溫度下,處理1小時~3天,藉此可製造本發明之縮合雜環衍生物(Id)。(Step 2-5) In an inert solvent (tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, etc.), a reagent such as diphenylcyanocarbamate (carbonimidate) is used in the base ( The amine compound ( 7 ) is treated in an ice-cold-reflux temperature for 1 hour in the presence of triethylamine, N,N-diisopropylethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, and the like. The condensed heterocyclic derivative (Id) of the present invention can be produced by ~3 days.
上述製法1或2中使用作為原料化合物的胺化合物(3 ),係例如可將市售品或依文獻記載之方法或組合一般合成手法之方法等所合成之硝基化合物(8 ),藉由一般還原法等進行還原而獲得。例如,可依以下製法3之方法進行製造。The amine compound ( 3 ) used as a raw material compound in the above Process 1 or 2 can be, for example, a commercially available product or a nitro compound ( 8 ) synthesized by a method described in the literature or a combination of a general synthesis method or the like. It is obtained by reduction by a general reduction method or the like. For example, it can be produced by the method of the following Process 3.
式中之環B、RB 、n、U、X係與上述同義。The ring B, R B , n, U, and X in the formula are synonymous with the above.
(步驟3)將硝基化合物(8 )之硝基,藉由一般之接觸還原法或金屬氫錯合物還原法等所進行之還原,則可製造胺化合物(3 )。接觸還原法係可例如於惰性溶媒(甲醇、乙醇、醋酸乙酯、四氫呋喃、醋酸等)中,使用觸媒(鈀碳粉末、銠碳粉末、鉑碳粉末等),使硝基化合物(8 )於一般為室溫~迴流溫度下,處理1小時~3天。金屬氫錯合物還原法係可例如於惰性溶媒(甲醇、乙醇、四氫呋喃等)中,使用還原劑(氫化硼鈉等),於添加劑(溴化鎳(II)等)存在下,使硝基化合物(8 )於一般為冰冷~室溫下,處理30分鐘~1天。(Step 3) The amine compound ( 3 ) can be produced by reduction of a nitro group ( 8 ) nitro group by a general contact reduction method or a metal hydrogen complex reduction method. The contact reduction method can be used, for example, in an inert solvent (methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, etc.), using a catalyst (palladium carbon powder, ruthenium carbon powder, platinum carbon powder, etc.) to make a nitro compound. ( 8 ) It is treated for 1 hour to 3 days at room temperature to reflux temperature. The metal hydrogen complex reduction method can be carried out, for example, in an inert solvent (methanol, ethanol, tetrahydrofuran, etc.) using a reducing agent (sodium borohydride or the like) in the presence of an additive (nickel (II) bromide or the like) to form a nitro group. The compound ( 8 ) is treated for 30 minutes to 1 day in an ice-cold room temperature.
尚且,在於上述製造方法中使用之化合物或所生成之化合物依反應條件而變化、或具有阻礙反應進行之官能基時,當然可使用從業者所慣用之適當保護基將其予以保護,並於適當階段予以去除。Further, in the case where the compound used in the above production method or the compound formed varies depending on the reaction conditions or has a functional group which hinders the progress of the reaction, it is of course possible to protect it with a suitable protecting group conventionally used by a practitioner, and suitably The stage is removed.
本發明之一般式(I)所示之縮合雜環衍生物,係可藉由依常法使前驅藥化試劑反應,而作成為其之羧基、羥基及/或胺基經轉換的前驅藥。又,本發明之一般式(I)所示之縮合雜環衍生物的前驅藥,係亦可為於「醫藥品之開發」第7卷分子設計163頁至198頁(廣川書店)所記載之生理條件下,轉換為本發明之化合物(I)者。The condensed heterocyclic derivative represented by the general formula (I) of the present invention can be converted into a precursor of a carboxyl group, a hydroxyl group and/or an amine group by reacting a procatalyst reagent by a usual method. Further, the prodrug of the condensed heterocyclic derivative represented by the general formula (I) of the present invention may be described in pp. 163-198 (Guangchuan Bookstore) of the molecular design of the "Development of Pharmaceutical Products", Volume 7. Under physiological conditions, it is converted to the compound (I) of the present invention.
一般式(I)所示之縮合雜環衍生物或其前驅藥,係可藉常法作成其藥理學上所容許的鹽。作為此種鹽,可舉例如鹽酸及硝酸等之無機酸鹽;醋酸及甲磺酸等之有機酸鹽;及鈉鹽及鉀鹽;N,N’-二苄基乙二胺及2-胺基乙醇等之有機鹼的加成鹽。The condensed heterocyclic derivative represented by the general formula (I) or a precursor thereof can be used as a pharmacologically acceptable salt by a usual method. Examples of such a salt include inorganic acid salts such as hydrochloric acid and nitric acid; organic acid salts such as acetic acid and methanesulfonic acid; and sodium and potassium salts; N,N'-dibenzylethylenediamine and 2-amine. An addition salt of an organic base such as ethanol.
一般式(I)所示之縮合雜環衍生物或其前驅藥中,於其之精製或造鹽過程中,有時將以水合物或溶媒合物的型式獲得。本發明之醫藥組成物,可使用縮合雜環衍生物或其前驅藥或其藥理學上所容許之鹽,或其水合物或溶媒合物的任一種。The condensed heterocyclic derivative represented by the general formula (I) or a precursor thereof may be obtained in the form of a hydrate or a solvent during the purification or salt formation thereof. The pharmaceutical composition of the present invention may be any one of a fused heterocyclic derivative or a precursor thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof.
再者,關於一般式(I)所示之縮合雜環衍生物或其前驅藥,亦有存在互變異構體、幾何異構體及/或光學異構體的情況,而本發明之醫藥組成物,可使用其任一種異構性,亦可使用其混合物。Further, regarding the condensed heterocyclic derivative represented by the general formula (I) or a precursor thereof, there are also cases in which tautomers, geometric isomers and/or optical isomers are present, and the pharmaceutical composition of the present invention Any one of them may be used, and a mixture thereof may also be used.
本發明之縮合雜環衍生物(I)係具有優越的GnRH拮抗作用,可調節性腺刺激荷爾蒙釋出荷爾蒙的作用,控制性腺刺激荷爾蒙及性荷爾蒙的產生、分泌。從而,本發明之縮合雜環衍生物(I)或其前驅藥或其藥理學上所容許之鹽、或其水合物或溶媒合物,可極有用地作為例如前列腺肥大症、子宮肌瘤、子宮內膜症、子宮纖維腫瘤、青春期早發症、無月經症、月經前症候群、月經困難症、多囊胞性卵巢症候群、紅斑性狼瘡、多毛症、侏儒症、睡眠障礙、青春痘、禿頭症、阿茲海默症、不孕症、過敏性腸症候群、前列腺癌、子宮癌、卵巢癌、乳癌及腦下垂體腫瘤之性荷爾蒙依存性疾病的預防或治療劑、生殖調節劑、避孕藥、排卵誘發劑、或性荷爾蒙依存性癌手術後再發預防劑等。The condensed heterocyclic derivative (I) of the present invention has superior GnRH antagonism, can regulate the action of the glandular hormone to stimulate the release of hormones, and control the production and secretion of hormones and sex hormones. Therefore, the condensed heterocyclic derivative (I) of the present invention or a precursor thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof thereof can be extremely useful as, for example, prostatic hypertrophy, uterine fibroids, Endometriosis, uterine fibroids, early onset of adolescence, no menstrual disease, premenstrual syndrome, menstrual difficulties, polycystic ovarian syndrome, lupus erythematosus, hirsutism, dwarfism, sleep disorders, acne, alopecia , Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, and pituitary tumors. Prevention or treatment of sexual hormone-dependent diseases, reproductive regulators, birth control pills, An ovulation-inducing agent, or a prophylactic agent for post-operative treatment of sex hormone-dependent cancer.
亦可將本發明之縮合雜環衍生物(I)或其前驅藥或其藥理學上所容許之鹽、或其水合物或溶媒合物,與所慣用之製劑載體予以混合而調製醫藥組成物。The condensed heterocyclic derivative (I) of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, may be mixed with a conventional preparation carrier to prepare a pharmaceutical composition. .
製劑載體係可配合後述的投予形態而適當地組合使用,可舉例如:乳糖等之賦形劑;硬脂酸鎂等之潤滑劑;羧基甲基纖維素等之崩解劑;羥基丙基甲基纖維素等之結合劑;聚乙二醇(macrogol)等之界面活性劑;碳酸氫鈉等之發泡劑;環糊精等之溶解輔助劑;檸檬酸等之酸味劑;乙底酸鈉等之安定化劑;磷酸鹽等之pH調整劑等。The preparation carrier may be appropriately used in combination with the administration form described later, and examples thereof include an excipient such as lactose; a lubricant such as magnesium stearate; a disintegrant such as carboxymethylcellulose; and a hydroxypropyl group; a binder such as methyl cellulose; a surfactant such as macrogol; a foaming agent such as sodium hydrogencarbonate; a dissolution aid such as cyclodextrin; a sour agent such as citric acid; A stabilizer for sodium or the like; a pH adjuster such as phosphate.
本發明之醫藥組成物的投予形態,可舉例如散劑、顆粒劑、細粒劑、乾糖漿劑、錠劑、膠囊劑等之經口投予劑;注射劑、貼片劑、拴劑等之非經口投予劑等;以經口投予劑為佳。The administration form of the pharmaceutical composition of the present invention may, for example, be an oral administration agent such as a powder, a granule, a fine granule, a dry syrup, a tablet or a capsule; an injection, a tablet, an elixir or the like. Non-oral administration agents, etc.; oral administration agents are preferred.
本發明之一般式(I)所示之化合物或其藥理學上所容許之鹽或其水合物或溶媒合物,最好依下述方式製造上述製劑:成人每一日,以經口投予劑依0.1~1000mg的範圍投予,以注射劑依0.01~100mg的範圍投予。The compound of the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, is preferably produced in the following manner: Adults are administered orally every day. The agent is administered in the range of 0.1 to 1000 mg, and the injection is administered in the range of 0.01 to 100 mg.
另外,本發明之醫藥組成物中,亦可再含有其他藥劑。作為此種藥劑,可舉例如:GnRH促效劑(例如,醋酸亮丙瑞林(Leuprorelin Acetate)、戈那瑞林(Gonadorelin)、布舍瑞林(Buserelin)、曲普瑞林(Triptorelin)、戈舍瑞林(Goserelin)、那法端林(Nafarelin)、組氨瑞林(Histrelin)、德舍瑞林(Deslorelin)、梅特瑞林(Meterelin)、雷舍瑞林(Lecirelin)等)、化學療法劑(例如,異磺磷胺(Ifosfamide)、阿霉素(Adriamycin)、培洛霉素(Peplomycin)、順鉑(Cisplatin)、環磷醯胺(Cyclophosphamide)、5-FU、UFT、甲氨喋呤(Methotrexate)、絲裂霉素(Mitomycin C)、米托蒽酮(Mitoxantron)、紫杉醇(Paclitaxel)、Dotaxel等)、胜肽性GnRH拮抗藥(例如,西曲瑞(Cetrorelix)、加尼瑞(Ganirelix)、阿巴瑞(Abarelix)、歐紮瑞(Ozarelix)、依茲瑞(Iturelix)、德加瑞(Degarelix)、替維瑞(Teverelix)等)、5 α-還原酶抑制劑(例如,非那甾胺(Finasteride)、度他雄胺(Dutasteride)等)、α腎上腺素受體抑制劑(例如,坦舒洛(Tamsulosin)、斯洛多(Silodosin)、烏拉地爾(Urapidil)等)、芳香酶抑制劑(例如,法倔唑(Fadrozole)、來曲唑(Letrozole)、阿納托唑(Anastrozole)、福美斯坦(Formestane)等)、副腎上腺系雄性素產生抑制劑(例如,利阿唑(Liarozole)等)、及荷爾蒙療法劑(例如,抗動情素劑(塔莫西芬(Tamoxifen)、氟維司群(Fulvestrant)等)、黃體荷爾蒙劑(安宮黃體酮(Medroxyprogesterone)等)、雄性素劑、動情素劑、抗雄性素劑(奧生多龍(Oxendolone)、氟他氨(Flutamide)、尼魯米特(Nilutamide)、比卡魯胺(bicalutamide)等)等)等。Further, the pharmaceutical composition of the present invention may further contain other pharmaceutical agents. As such an agent, for example, a GnRH agonist (for example, Leuprorelin Acetate, Gonadorelin, Buserelin, Triptorelin, Goserelin, Nafarelin, Histrelin, Deslorelin, Meterelin, Lecirelin, etc. Chemotherapeutic agents (eg, Ifosfamide, Adriamycin, Peplomycin, Cisplatin, Cyclophosphamide, 5-FU, UFT, A Methotrexate, Mitomycin C, Mitoxantron, Paclitaxel, Dotaxel, etc., peptide GnRH antagonists (eg, cetrix) (Cetrorelix), Canary (Ganirelix), Abari (Abarelix), Ozar (Ozarelix), Izre (Iturelix), De Garry (Degarelix), Teveri (Teverelix), etc., 5 alpha-reductase inhibitors (eg, Finasteride, Dutasteride, etc.), alpha adrenergic receptor inhibitors (eg, stansulo (Tamsulosin), Slodo (Silodosin), Urapidil, etc., aromatase inhibitors (for example, Fadrozole, Letrozole, Anastrozole, Formestane, etc.), deputy Adrenal androgen production inhibitors (eg, Liarozole, etc.), and hormonal therapies (eg, anti-alrading agents (Tamoxifen, Fulvestrant, etc.), corpus luteum Hormone (Medroxyprogesterone, etc.), male, emollient, anti-androgen (Oxendolone, Flutamide, Nilutamide, ratio) Bicalutamide, etc.), etc.
藉以下實施例及試驗體更加詳細地說明本發明內容,但本發明並不限定於其內容。The present invention will be described in more detail by way of the following examples and test examples, but the invention is not limited thereto.
2-氯-5-(3,4-二氫喹啉-1(2H)-基磺醯基)苯胺於1,2,3,4-四氫喹啉(3.12g)及碳酸氫鈉(2.66g)之四氫呋喃(60mL)懸濁液中依序加入水(60mL)及4-氯-3-硝基苯磺醯氯(5.4g)的四氫呋喃(30mL)溶液,於室溫下攪拌一夜。將反應混合物以醋酸乙酯稀釋,依序以水、1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,得到1-[(4-氯-3-硝基苯基)磺醯基]-1,2,3,4-四氫喹啉(5.0g)。將此溶解於四氫呋喃(45mL),於冰冷下加入甲醇(45mL)、溴化鎳(II)(0.15g)及氫化硼鈉(1.61g),於同溫度下攪拌30分鐘,接著於室溫下攪拌30分鐘。將反應混合物以醋酸乙酯稀釋,依序以飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=3/1)進行精製而得到目標化合物(4.33g)。2-Chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)aniline in 1,2,3,4-tetrahydroquinoline (3.12g) and sodium bicarbonate (2.66) A solution of water (60 mL) and 4-chloro-3-nitrobenzenesulfonium chloride (5.4 g) in tetrahydrofuran (30 mL) was added to EtOAc EtOAc m. The reaction mixture was diluted with ethyl acetate, washed with water, 1 mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-[(4-chloro-3-nitrophenyl)sulfonyl]-1,2,3,4-tetrahydroquinoline (5.0 g). This was dissolved in tetrahydrofuran (45 mL), and methanol (45 mL), nickel (II) bromide (0.15 g) and sodium borohydride (1.61 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, then at room temperature Stir for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3/1) to give the title compound (4.33 g).
使用對應的原料物質,依與參考例1相同的方法,得到表1~2記載之參考例2~11的化合物。Using the corresponding starting materials, the compounds of Reference Examples 2 to 11 described in Tables 1 to 2 were obtained in the same manner as in Reference Example 1.
2-氯-5-(3,4-二氫喹啉-1(2H)-基甲基)苯胺在冰冷下於4-氯-3-硝基苄基醇(1g)之二氯甲烷(10mL)溶液中加入三乙基胺(1.21mL)及甲磺醯氯(0.5mL),於室溫下攪拌10小時。將反應混合物以醋酸乙酯稀釋,依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,得到甲磺醯酸(4-氯-3-硝基苄基)(1.08g)。將此溶解於乙腈(4mL)-乙醇(4mL)中,加入1,2,3,4-四氫喹啉(1.62g)及觸媒量之碘化鈉,於60℃下攪拌一夜。將反應混合物以醋酸乙酯稀釋,依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=3/1)進行精製而得到1-(4-氯-3-硝基苄基)-1,2,3,4-四氫喹啉(1.22g)。將此溶解於四氫呋喃(12mL),於冰冷下加入甲醇(12mL)、溴化鎳(II)(44mg)及氫化硼鈉(0.46g),於同溫度下攪拌30分鐘,接著於室溫下攪拌30分鐘。將反應混合物以醋酸乙酯稀釋,依序以飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=3/1)進行精製而得到目標化合物(0.79g)。Dichloro-5-(3,4-dihydroquinolin-1(2H)-ylmethyl)aniline in 4-chloro-3-nitrobenzyl alcohol (1 g) in dichloromethane (10 mL) To the solution were added triethylamine (1.21 mL) and methanesulfonyl chloride (0.5 mL), and stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give methanesulfonic acid (4-chloro-3-nitrobenzyl) (1.08 g). This was dissolved in acetonitrile (4 mL)-ethanol (4 mL), and 1,2,3,4-tetrahydroquinoline (1.62 g) and a solvent amount of sodium iodide were added thereto, and the mixture was stirred at 60 ° C overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3 / 1) to give 1-(4-chloro-3). -Nitrobenzyl)-1,2,3,4-tetrahydroquinoline (1.22 g). This was dissolved in tetrahydrofuran (12 mL), and methanol (12 mL), nickel (II) bromide (44 mg) and sodium borohydride (0.46 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, followed by stirring at room temperature. 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3/1) to give the title compound (0.79 g).
3-苄基氧基-6-氯苯胺將4-氯-3-硝基苯(0.13g)溶解於N,N-二甲基甲醯胺(3mL)中,加入碳酸鉀(0.31g)及溴化苄基(0.14mL),於室溫下攪拌2小時。將反應混合物以二乙基醚稀釋,依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,使殘渣溶解於四氫呋喃(3mL),於冰冷下加入甲醇(3mL)、溴化鎳(II)(8mg)及氫化硼鈉(85mg),於同溫度下攪拌30分鐘,接著於室溫下攪拌30分鐘。將反應混合物以醋酸乙酯稀釋,依序以飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,得到目標化合物(0.15g)。4-Benzyloxy-6-chloroaniline 4-chloro-3-nitrobenzene (0.13g) was dissolved in N,N-dimethylformamide (3mL), potassium carbonate (0.31g) The benzyl bromide (0.14 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL), and methanol (3 mL), nickel (II) bromide (8 mg) and sodium borohydride (85 mg) were added under ice cooling, and stirred at the same temperature 30 After a minute, it was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (0.15 g).
使用對應的原料物質,依與參考例13相同的方法,得到表2記載之參考例14~17的化合物。Using the corresponding starting materials, the compounds of Reference Examples 14 to 17 shown in Table 2 were obtained in the same manner as in Reference Example 13.
3-(2-苯基乙基)苯胺將3-溴化硝基苯(1g)、苯乙烯(1.7mL)、醋酸鈀(II)(95mg)、參(2-甲基苯基)膦(0.3g)及N,N-二異丙基胺(5mL)的混合物加熱迴流24小時。將反應混合物以二乙基醚稀釋,依序以1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=10/1)進行精製而得到3-((E)-2-苯基乙烯基)硝基苯(0.76g)。將所得之3-((E)-2-苯基乙烯基)硝基苯(0.26g)之甲醇(10mL)溶液中加入10%鈀碳粉末(50mg),於氫氣體環境下於室溫攪拌2小時。濾去不溶物,將濾液於減壓下進行濃縮而得到目標化合物(0.22g)。3-(2-Phenylethyl)aniline 3-bromonitrobenzene (1 g), styrene (1.7 mL), palladium (II) acetate (95 mg), ginseng (2-methylphenyl)phosphine ( A mixture of 0.3 g) and N,N-diisopropylamine (5 mL) was heated to reflux for 24 hours. The reaction mixture was diluted with diethyl ether, washed with 1 mol/L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1) to give 3-((E)-2 -Phenylvinyl)nitrobenzene (0.76 g). Add 10% palladium carbon powder (50 mg) to a solution of 3-((E)-2-phenylvinyl)nitrobenzene (0.26 g) in methanol (10 mL) at room temperature under hydrogen atmosphere Stir for 2 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g).
2-胺基噻吩-3,4-二羧酸二乙酯於硫黃(6.9g)、丙酮酸乙酯(25g)及氰基醋酸乙酯(24.4g)之N,N-二甲基甲醯胺(130mL)混合物中,於室溫下歷時30分鐘加入三乙基胺(21.8g),將反應混合物於50℃下攪拌2小時。於反應混合物中加入水(1L)及飽和食鹽水(50mL),並以二乙基醚(250mL)萃取3次。將萃取物以無水硫酸鎂進行乾燥,以二氧化矽凝膠管柱層析法(洗提溶媒:二乙基醚)進行精製而得到目標化合物(28.2g)。N,N-dimethyl group of diethyl 2-aminothiophene-3,4-dicarboxylate in sulfur (6.9 g), ethyl pyruvate (25 g) and ethyl cyanoacetate (24.4 g) Triethylamine (21.8 g) was added to a mixture of decylamine (130 mL) at room temperature over 30 min and the reaction mixture was stirred at 50 ° C for 2 hr. Water (1 L) and saturated brine (50 mL) were added to the mixture, and the mixture was extracted three times with diethyl ether (250 mL). The extract was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography (eluent solvent: diethyl ether) to give the title compound (28.2 g).
1-(2-氟-6-甲氧基苯基)乙醇於2-氟-6-甲氧基苯醛(0.5g)之四氫呋喃(10mL)溶液中,於-78℃下加入甲基鋰(1.15mol/L二乙基醚溶液,3.4mL),於同溫度下攪拌1小時,接著於室溫下攪拌30分鐘。於反應混合物中加入飽和氯化銨水溶液,以二乙基醚進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除,得到目標化合物(0.45g)。1-(2-Fluoro-6-methoxyphenyl)ethanol was added to a solution of 2-fluoro-6-methoxybenzaldehyde (0.5 g) in tetrahydrofuran (10 mL). 1.15 mol/L diethyl ether solution, 3.4 mL), stirred at the same temperature for 1 hour, followed by stirring at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with diethyl ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.45 g).
2-氟-5-[1-(2-氟-6-甲氧基苯基)乙氧基]苯胺於4-氟-3-硝基苯(依國際公開WO97/39064記載之方法合成)(0.2g)、1-(2-氟-6-甲氧基苯氧)乙醇(0.22g)及三苯基膦(0.4g)之四氫呋喃(1.5mL)溶液中在室溫下加入偶氮二羧酸二異丙酯(40%甲苯溶液、0.84mL),於室溫下攪拌2小時。將反應混合物於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=8/1)進行精製而得到2-氟-5-[1-(2-氟-6-甲氧基苯基)乙氧基]-1-硝基苯(0.15g)。將此溶解於四氫呋喃(3mL),於冰冷下加入甲醇(3mL)、溴化鎳(II)(5mg)及氫化硼鈉(55mg),於同溫度下攪拌30分鐘,接著於室溫下攪拌30分鐘。將反應混合物以醋酸乙酯稀釋,依序以飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=3/1)進行精製而得到目標化合物(0.11g)。2-Fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenylamine in 4-fluoro-3-nitrobenzene (synthesized according to the method described in International Publication WO97/39064) Add azodicarboxylate at room temperature in a solution of 0.2 g), 1-(2-fluoro-6-methoxyphenoxy)ethanol (0.22 g) and triphenylphosphine (0.4 g) in tetrahydrofuran (1.5 mL) Diisopropyl acid (40% in toluene, 0.84 mL) was stirred at room temperature for 2 hours. The reaction mixture was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 8/1) to give 2-fluoro- 5-[1-(2-Fluoro-6-methoxyphenyl)ethoxy]-1-nitrobenzene (0.15 g). This was dissolved in tetrahydrofuran (3 mL), and methanol (3 mL), nickel (II) bromide (5 mg) and sodium borohydride (55 mg) were added under ice cooling, and stirred at the same temperature for 30 minutes, followed by stirring at room temperature 30 minute. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3 / 1) to give the title compound (0.11 g).
使用對應的原料物質,依與參考例13或參考例21相同的方法,得到表3~4記載之參考例22~29的化合物。Using the corresponding starting materials, the compounds of Reference Examples 22 to 29 shown in Tables 3 to 4 were obtained in the same manner as in Reference Example 13 or Reference Example 21.
1-[4-氟-3-(第三丁氧基羰基胺基)苯基]-2-甲基-1-丙烷於濃硫酸(10mL)在-20℃下加入1-(4-氟苯基)-2-甲基-1-丙烷(2.92g),於同溫度下攪拌15分鐘。於-20℃下加入發煙硝酸(1.4mL)及濃硫酸(4.2mL)的混合物,於同溫度下攪拌20分鐘。於反應混合物中加入冰(100g),於攪拌下升溫至室溫。將反應混合物以醋酸乙酯進行萃取,將萃取物依序以水(3次)、飽和碳酸氫鈉水溶液(2次)、及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=95/5~85/15)進行精製而得到1-(4-氟-3-硝基苯基)-2-甲基-1-丙烷(1.8g)。將此溶解於乙醇(5mL),加入10%鈀碳粉末(0.36g),於氫氣環境下,在室溫下攪拌2小時。濾去不溶物,將濾液於減壓下進行濃縮。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=90/10~83/17)進行精製而得到1-(3-胺基-4-氟苯基)-2-甲基-1-丙烷(1.45g)。將此溶解於四氫呋喃(33mL),加入4-二甲基胺基吡啶(0.29g)及二(第三丁基)二碳酸酯(3.49g),加熱迴流1.5小時。將反應混合物注入至0.5mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物以水及飽和食鹽水依序洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=95/5)進行精製而得到1-{4-氟-3-[N,N-二(第三丁氧基羰基)胺基]苯基}-2-甲基-1-丙烷(1.8g)。將此溶解於甲醇(15mL),加入碳酸鉀(1.96g),於60℃攪拌30分鐘。將反應混合物冷卻至室溫,加入水及飽和食鹽水,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=5/1)進行精製而得到目標化合物(1.14g)。1-[4-Fluoro-3-(t-butoxycarbonylamino)phenyl]-2-methyl-1-propane was added to concentrated sulfuric acid (10 mL) at -20 ° C. 2-methyl-1-propane (2.92 g) was stirred at the same temperature for 15 minutes. A mixture of fuming nitric acid (1.4 mL) and concentrated sulfuric acid (4.2 mL) was added at -20 ° C and stirred at the same temperature for 20 min. Ice (100 g) was added to the reaction mixture, and the mixture was warmed to room temperature with stirring. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water (3 times), saturated aqueous sodium hydrogencarbonate (2 times), and brine, and dried over anhydrous sodium sulfate. Distilled under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 95/5 to 85/15) to give 1-(4-fluoro-3-nitrophenyl) )-2-methyl-1-propane (1.8 g). This was dissolved in ethanol (5 mL), and 10% palladium carbon powder (0.36 g) was added thereto, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 90/10 to 83/17) to give 1-(3-amino-4-fluorophenyl). )-2-methyl-1-propane (1.45 g). This was dissolved in tetrahydrofuran (33 mL), and 4-dimethylaminopyridine (0.29 g) and di(t-butyl)dicarbonate (3.49 g) were added, and the mixture was refluxed for 1.5 hr. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 95/5) to give 1-{4-fluoro-3-[N,N- Bis(t-butoxycarbonyl)amino]phenyl}-2-methyl-1-propane (1.8 g). This was dissolved in methanol (15 mL), potassium carbonate (1.96 g) was added, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was cooled to room temperature, and water and brine were added, and ethyl acetate was evaporated. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 5 / 1) to give the title compound (1.14 g).
1-(3-胺基-4-氟苯基)-2-(5-氟-2-甲氧基苯基)-2-甲基-1-丙烷將1-[4-氟-3-(第三丁氧基羰基胺基)苯基]-2-甲基-1-丙烷(0.11g)、2-溴-4-氟苯甲醚(0.057mL)、醋酸鈀(II)(4.5mg)、四氟硼酸三(第三丁基)膦(5.8mg)及第三丁氧鈉(96mg)之四氫呋喃(1mL)混合物於氬氣環境下在70℃攪拌3天。於反應混合物中加水攪拌10分鐘後,將混合物注入至1mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物以水及飽和食鹽水依序洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=10/1)進行精製而得到1-[4-氟-3-(第三丁氧基羰基胺基)苯基]-2-(5-氟-2-甲氧基苯基)-2-甲基-1-丙烷(45mg)。將此溶解於鹽酸(4mol/L醋酸乙酯溶液,3mL),於室溫攪拌一夜。將反應混合物注入至飽和碳酸氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以胺基丙基二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=4/1~3/1)進行精製而得到目標化合物(25mg)。1-(3-Amino-4-fluorophenyl)-2-(5-fluoro-2-methoxyphenyl)-2-methyl-1-propane 1-[4-fluoro-3-( Third butoxycarbonylamino)phenyl]-2-methyl-1-propane (0.11 g), 2-bromo-4-fluoroanisole (0.057 mL), palladium(II) acetate (4.5 mg) A mixture of tris(tert-butyl)phosphine tetrafluoroborate (5.8 mg) and sodium tributoxide (96 mg) in tetrahydrofuran (1 mL) was stirred at 70 ° C for 3 days under argon. After stirring with water for 10 minutes in the reaction mixture, the mixture was poured into 1 mol/L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1) to give 1-[4-fluoro-3-(t-butoxycarbonylamine) Phenyl]-2-(5-fluoro-2-methoxyphenyl)-2-methyl-1-propane (45 mg). This was dissolved in hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL) and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by an aminopropyl sulfonium chloride column chromatography (eluent solvent: n-hexane / ethyl acetate = 4/1 to 3/1) to give the title compound (25 mg).
使用對應的原料物質,依與參考例31相同的方法,得到表4~5記載之參考例32~35的化合物。Using the corresponding starting materials, the compounds of Reference Examples 32 to 35 shown in Tables 4 to 5 were obtained in the same manner as in Reference Example 31.
3-(1-苯基乙基硫)苯胺於3-巰基苯胺(1g)及碳酸鉀(1.21g)之N,N-二甲基甲醯胺(20mL)混合物中加入1-苯基乙基溴(1.2mL),於室溫下攪拌2小時。於反應混合物中加入水,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(1.78g)。1-(1-Phenylethylthio)aniline 1-methoxyethyl was added to a mixture of 3-mercaptoaniline (1 g) and potassium carbonate (1.21 g) in N,N-dimethylformamide (20 mL) Bromine (1.2 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 1 / 1) to give the title compound (1.78 g).
使用對應的原料物質,依與參考例36相同的方法,得到表5記載之參考例37的化合物。Using the corresponding starting material, the compound of Reference Example 37 shown in Table 5 was obtained in the same manner as in Reference Example 36.
3-(1-甲基-1-苯基乙基硫)苯胺於水(1.6mL)-濃硫酸(1.6mL)混合溶液中加入3-硝基硫酚(0.5g),於室溫下攪拌1小時。於混合物中加入α-甲基苯乙烯(0.38g)之四氫呋喃(1.6mL)溶液,於室溫下攪拌30分鐘。將反應混合物注入至冰水中,以醋酸乙酯進行萃取。將萃取物以水、飽和碳酸氫鈉水溶液及飽和食鹽水依序洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=3/2)進行精製而得到3-(1-甲基-1-苯基乙基硫)硝基苯(0.88g)。將此溶解於四氫呋喃(10mL)中,於冰冷下加入甲醇(10mL)、溴化鎳(II)(35mg)及氫化硼鈉(0.37g),於同溫度下攪拌30分鐘,接著於室溫攪拌1小時。將反應混合物以醋酸乙酯稀釋,依序以飽和碳氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=3/2)進行精製而得到目標化合物(0.69g)。Add 3-nitrothiophenol (0.5g) to a mixed solution of 3-(1-methyl-1-phenylethylthio)aniline in water (1.6mL)-concentrated sulfuric acid (1.6mL), stir at room temperature 1 hour. A solution of α-methylstyrene (0.38 g) in tetrahydrofuran (1.6 mL) was added to the mixture and stirred at room temperature for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 3/2) to give 3-(1-methyl-1-phenylethyl). Sulfur) nitrobenzene (0.88 g). This was dissolved in tetrahydrofuran (10 mL), and methanol (10 mL), nickel (II) bromide (35 mg) and sodium borohydride (0.37 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, followed by stirring at room temperature. 1 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to give the title compound (0.69 g). ).
3-胺基-4-氟-N-甲基-N-苯基苯醯胺於4-氟-3-硝基苯甲酸(2g)之二氯甲烷(50mL)溶液中加入N,N-二甲基甲醯胺(0.01mL)及草醯氯(6.86g),於室溫下攪拌1小時。於反應混合物於減壓下進行濃縮。將殘渣之四氫呋喃(10mL)溶液加入至N-甲基苯胺(1.22g)及碳酸氫鈉(2.72g)之四氫呋喃(20mL)混合物中,於室溫下攪拌一夜。將反應混合物注入至水中,以醋酸乙酯進行萃取。將萃取物以1mol/L鹽酸、水及飽和食鹽水依序洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除,得到4-氟-3-硝基-N-甲基-N-苯基苯醯胺(2.95g)。將此溶解於四氫呋喃(50mL)中,於冰冷下加入甲醇(50mL)、溴化鎳(II)(0.12g)及氫化硼鈉(1.26g),於同溫度下攪拌30分鐘,接著於室溫攪拌30分鐘。將反應混合物注入至飽和碳氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(2.33g)。3-Amino-4-fluoro-N-methyl-N-phenylbenzamide was added to a solution of 4-fluoro-3-nitrobenzoic acid (2 g) in dichloromethane (50 mL). Methylformamide (0.01 mL) and grass chloroform (6.86 g) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran (10 mL) was added to a mixture of N-methylaniline (1.22 g) and sodium hydrogencarbonate (2.72 g) in THF (20 mL). The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-fluoro-3-nitro-N-methyl -N-Phenylbenzamide (2.95 g). This was dissolved in tetrahydrofuran (50 mL), and methanol (50 mL), nickel (II) bromide (0.12 g) and sodium borohydride (1.26 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, then at room temperature Stir for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (2.33 g).
使用對應的原料物質,依與參考例39相同的方法,得到表5記載之參考例40的化合物。Using the corresponding starting material, the compound of Reference Example 40 shown in Table 5 was obtained in the same manner as in Reference Example 39.
使用對應的原料物質,依與參考例21相同的方法,得到表5記載之參考例41~42的化合物。Using the corresponding starting materials, the compounds of Reference Examples 41 to 42 shown in Table 5 were obtained in the same manner as in Reference Example 21.
4-氟-2-甲氧基-5-硝基苯磺醯氯將3-氟-4-硝基苯(2.56g)、碳酸鉀(4.5g)及碘化甲基(4.63g)之N,N-二甲基甲醯胺(15mL)混合物於室溫下攪拌一夜。將反應混合物注入至水中,以二乙基醚予以洗淨。將萃取物以水洗淨2次後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除,得到3-氟-4-硝基苯甲醚(2.56g)。將此溶解於1,2-二氯乙烷(13mL)中,於冰冷下加入氯磺酸(1.3mL),加熱迴流4小時。將反應混合物以二氯甲烷稀釋,依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=2/1)進行精製而得到目標化合物(0.51g)。4-fluoro-2-methoxy-5-nitrobenzenesulfonium chloride 3-N-fluoro-4-nitrobenzene (2.56 g), potassium carbonate (4.5 g) and methyl iodide (4.63 g) The mixture of N-dimethylformamide (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into water and washed with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3-fluoro-4-nitroanisole (2.56 g). This was dissolved in 1,2-dichloroethane (13 mL), and chlorosulfonic acid (1.3 mL) was added under ice cooling, and the mixture was refluxed for 4 hr. The reaction mixture was diluted with methylene chloride, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 2 / 1) to give the title compound (0.51 g).
使用對應的原料物質,依與參考例1相同的方法,得到表6~9記載之參考例44~69的化合物。Using the corresponding starting materials, the compounds of Reference Examples 44 to 69 shown in Tables 6 to 9 were obtained in the same manner as in Reference Example 1.
4-胺基-5-甲基噻吩-2,3-二羧酸二甲基鹽酸鹽於甲醇(15mL)中在冰冷下加入鈉(0.38g),於同溫下攪拌至鈉溶解。於反應混合物中加入2-巰基丙酸乙酯(1.81g)及丁烯酸二甲酯(2.17g),加熱迴流3小時。將反應混合物冷卻至室溫後,加入水(100mL),以二乙基醚進行洗淨。將水層冰冷,加入2mol/L鹽酸使其呈酸性,以醋酸乙酯萃取2次。組合萃取物,以飽和食鹽水洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=4/1~3/1)進行精製而得到5-甲基-4-側氧基-2,3-雙甲氧基羰基四氫噻吩(2.68g)。將此溶解於甲醇(8mL),加入氯化羥基銨(0.92g),加熱迴流2小時。將反應混合物冷卻至室溫後,加入醋酸乙酯(24mL)並攪拌10分鐘。濾取析出物,以醋酸乙酯洗淨後,於減壓下進行乾燥而得到目標化合物(0.77g)。4-Amino-5-methylthiophene-2,3-dicarboxylic acid dimethyl hydrochloride was added to sodium (0.38 g) in methanol (15 mL) under ice cooling, and stirred at the same temperature until sodium was dissolved. Ethyl 2-mercaptopropionate (1.81 g) and dimethyl crotonate (2.17 g) were added to the reaction mixture, and the mixture was heated to reflux for 3 hr. After the reaction mixture was cooled to room temperature, water (100 mL) was added and washed with diethyl ether. The aqueous layer was ice-cooled, made acidic by adding 2 mol/L hydrochloric acid, and extracted twice with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 4/1 to 3/1) to give 5-methyl-4- oxo-2. 3-bismethoxycarbonyltetrahydrothiophene (2.68 g). This was dissolved in methanol (8 mL), hydroxyammonium chloride (0.92 g) was added, and the mixture was refluxed for 2 hr. After the reaction mixture was cooled to room temperature, ethyl acetate (24 mL) was added and stirred for 10 min. The precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (0.77 g).
使用對應的原料物質,依與參考例30相同的方法,得到表9記載之參考例71~72的化合物。Using the corresponding starting materials, the compounds of Reference Examples 71 to 72 shown in Table 9 were obtained in the same manner as in Reference Example 30.
使用對應的原料物質,依與參考例31相同的方法,得到表9~10記載之參考例73~77的化合物。Using the corresponding starting materials, the compounds of Reference Examples 73 to 77 shown in Tables 9 to 10 were obtained in the same manner as in Reference Example 31.
4-溴-2-(第三丁氧基羰基胺基)-1-氟苯於1-溴-4-氟-3-硝基苯(1.56g)、溴化鎳(II)(78mg)、甲醇(28mL)及四氫呋喃(28mL)之混合物中在冰冷下加入氫化硼鈉(805mg),於同溫下攪拌30分鐘、及於室溫下攪拌30分鐘後,將反應混合物注入至飽和碳酸氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除,得到5-溴-2-氟苯胺(1.3g)。將此溶解於四氫呋喃(30mL)中,加入4-二甲基胺基吡啶(0.26g)及二(第三丁基)二碳酸酯(3.1g),加熱迴流1.5小時。將反應混合物注入至0.5mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。於殘渣中加入甲醇(21mL)及碳酸鉀(2.94g),加熱迴流2小時。於反應混合物中加入水後,注入至飽和食鹽水中,以醋酸乙酯進行萃取。將萃取物以無水硫酸鈉進行乾燥後,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=95/5)進行精製而得到目標化合物(1.72g)。4-bromo-2-(t-butoxycarbonylamino)-1-fluorobenzene in 1-bromo-4-fluoro-3-nitrobenzene (1.56 g), nickel (II) bromide (78 mg), A mixture of methanol (28 mL) and tetrahydrofuran (28 mL) was added to sodium borohydride (805 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes, and stirred at room temperature for 30 minutes, and then the reaction mixture was poured into saturated sodium hydrogencarbonate. In an aqueous solution, extraction was carried out with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-fluoroaniline (1.3 g). This was dissolved in tetrahydrofuran (30 mL), and 4-dimethylaminopyridine (0.26 g) and di(t-butyl)dicarbonate (3.1 g) were added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Methanol (21 mL) and potassium carbonate (2.94 g) were added to the residue, and the mixture was refluxed for 2 hr. After water was added to the reaction mixture, it was poured into a saturated saline solution and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 95/5) to give the title compound (1.72 g).
2-(3-胺基-4-氟苯基)-1-(2-甲氧基苯基)-2-甲基-1-丙烷將1-(2-甲氧基苯基)-2-甲基-1-丙烷(0.58g)、4-溴-2-(第三丁氧基羰基胺基)-1-氟苯(0.94g)、醋酸鈀(II)(37mg)、四氟硼酸三(第三丁基)膦(47mg)及第三丁氧鈉(0.78g)之四氫呋喃(10mL)之混合物,在氬氣環境下於60℃攪拌一夜。於反應混合物中加入水攪拌10分鐘後,將混合物注入至1mol/L鹽酸中,以二乙基醚進行萃取。將萃取物依序以水及飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=95/5~85/15)進行精製而得到2-[3-(第三丁氧基羰基胺基)-4-氟苯基]-1-(2-甲氧基苯基)-2-甲基-1-丙烷(0.91g)。於所得之2-[3-(第三丁氧基羰基胺基)-4-氟苯基]-1-(2-甲氧基苯基)-2-甲基-1-丙烷(0.34g)中加入鹽酸(4mol/L醋酸乙酯溶液,3mL),於室溫攪拌3小時。將反應混合物注入至飽和碳酸氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除而得到目標化合物(0.22g)。2-(3-Amino-4-fluorophenyl)-1-(2-methoxyphenyl)-2-methyl-1-propane 1-(2-methoxyphenyl)-2- Methyl-1-propane (0.58g), 4-bromo-2-(t-butoxycarbonylamino)-1-fluorobenzene (0.94g), palladium acetate (II) (37mg), tetrafluoroborate A mixture of (t-butyl)phosphine (47 mg) and sodium tributoxide (0.78 g) in tetrahydrofuran (10 mL) was stirred overnight at 60 ° C under argon. After adding water to the reaction mixture and stirring for 10 minutes, the mixture was poured into 1 mol/L hydrochloric acid, and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 95/5 to 85/15) to give 2-[3-(t-butoxycarbonylamine) 4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propane (0.91 g). 2-[3-(Tertibutoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propane (0.34 g) obtained Hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.22 g).
使用對應的原料物質,依與參考例79相同的方法,得到表10記載之參考例80~81的化合物。Using the corresponding starting materials, the compounds of Reference Examples 80 to 81 shown in Table 10 were obtained in the same manner as in Reference Example 79.
使用苯取代4-氟-3-硝基苯,並使用4-氯-3-硝基苄基醇取代1-(2-氟-6-甲氧基苯基)乙醇,依與參考例21相同的方法,得到表11記載之參考例82的化合物。Substituting benzene for 4-fluoro-3-nitrobenzene and replacing 4-(2-fluoro-6-methoxyphenyl)ethanol with 4-chloro-3-nitrobenzyl alcohol, as in Reference Example 21 The compound of Reference Example 82 shown in Table 11 was obtained.
2-氯-5-(2-苯基乙基)苯胺於4-氯-3-硝基苯醛(1g)及苄基三苯基溴化鏻(2.34g)的甲苯(35mL)懸濁液中加入氫化鈉(55%,0.28g),於室溫下攪拌一夜。於反應混合物中加入1mol/L鹽酸,以二氯甲烷進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=10/1)進行精製而得到2-氯-5-((Z)-2-苯基乙烯基)-1-硝基苯(0.79g)。將所得之2-氯-5-((Z)-2-苯基乙烯基)-1-硝基苯(0.16g)溶解於乙醇(6mL)-甲醇(2mL)中,加入5%銠碳粉末(20mg)及啉(5mg),於氫氣環境下在室溫下攪拌一夜。濾除不溶物,將濾液在減壓下進行濃縮。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=5/1)進行精製而得到目標化合物(87mg)。2-Chloro-5-(2-phenylethyl)aniline in 4-chloro-3-nitrobenzaldehyde (1 g) and benzyltriphenylphosphonium bromide (2.34 g) in toluene (35 mL) suspension Sodium hydride (55%, 0.28 g) was added and stirred at room temperature overnight. 1 mol/L hydrochloric acid was added to the reaction mixture, and extraction was carried out with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1) to give 2-chloro-5-((Z)-2-phenylvinyl )-1-nitrobenzene (0.79 g). The obtained 2-chloro-5-((Z)-2-phenylvinyl)-1-nitrobenzene (0.16 g) was dissolved in ethanol (6 mL)-methanol (2 mL), and 5% 铑 powder was added. End (20mg) and The porphyrin (5 mg) was stirred at room temperature overnight under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 5 / 1) to give the title compound (87 mg).
1-(第三丁氧基羰基胺基)-5-乙炔基-2-氟苯將4-溴-2-(第三丁氧基羰基胺基)-1-氟苯(0.57g)、三甲基矽烷基乙炔(0.55mL)、肆(三苯基膦)鈀(0)(23mg)及碘化銅(I)(7mg)之N,N-二異丙基胺(5.7mL)混合物,於80℃下攪拌一夜。將反應混合物冷卻至室溫後,以二乙基醚進行稀釋。濾除不溶物,將濾液在減壓下進行濃縮。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=15/1)進行精製而得到1-(第三丁氧基羰基胺基)-2-氟-5-三甲基矽烷基乙炔基苯(0.6g)。將此溶解於四氫呋喃(10mL)中,加入四(正丁基)氟化銨(1mol/L四氫呋喃溶液,2.4mL),於室溫下攪拌1小時。使反應混合物在減壓下進行濃縮,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=20/1~10/1)進行精製而得到目標化合物(0.34g)。1-(Tertibutoxycarbonylamino)-5-ethynyl-2-fluorobenzene 4-bromo-2-(t-butoxycarbonylamino)-1-fluorobenzene (0.57 g), three a mixture of methyl decyl acetylene (0.55 mL), hydrazine (triphenylphosphine) palladium (0) (23 mg) and copper (I) iodide (7 mg) in N,N-diisopropylamine (5.7 mL). Stir at 80 ° C overnight. After cooling the reaction mixture to room temperature, it was diluted with diethyl ether. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 15 / 1) to give 1-(t-butoxycarbonylamino)-2-fluoro- 5-trimethyldecyl ethynylbenzene (0.6 g). This was dissolved in tetrahydrofuran (10 mL), and tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 2.4 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 20/1 to 10/1) to give the title compound ( 0.34g).
2-溴-3,4-二氟苯甲醚於3,4-二氟苯甲醚(2mL)之四氫呋喃(50mL)溶液中,在-78℃下加入正丁氧鋰(2.67mol/L正己烷溶液,6.95mL),於同溫下攪拌30分鐘。於反應混合物中加入溴(1.04mL),於-78℃下攪拌15分鐘及於冰冷下攪拌1小時。於反應混合物中加入飽和氯化銨水溶液,以二乙基醚進行萃取。將萃取物依序以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=9/1)進行精製而得到目標化合物(0.91g)。2-Bromo-3,4-difluoroanisole was added to a solution of 3,4-difluoroanisole (2 mL) in tetrahydrofuran (50 mL), and n-butoxy lithium (2.67 mol/L hexane) was added at -78 °C. The alkane solution, 6.95 mL) was stirred at the same temperature for 30 minutes. Bromine (1.04 mL) was added to the reaction mixture, stirred at -78 °C for 15 min and stirred for 1 hour under ice cold. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 9/1) to give the title compound (0.91 g).
2-氟-5-(2-苯基乙基)苯胺將1-(第三丁氧基羰基胺基)-5-乙炔基-2-氟苯(0.11g)、碘苯(0.1g)、肆(三苯基膦)鈀(0)(16mg)及碘化銅(I)(5mg)之N,N-二異丙基胺(2mL)混合物於室溫下攪拌一夜。將反應混合物以醋酸乙酯進行稀釋,濾除不溶物,將濾液在減壓下進行濃縮。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=10/1)進行精製而得到1-(第三丁氧基羰基胺基)-2-氟-5-苯基乙炔基苯(0.14g)。將此溶解於醋酸乙酯(3mL)中,加入10%鈀碳粉末(50mg),在氫氣環境下於室溫下攪拌2小時。濾除不溶物,將濾液在減壓下進行濃縮而得到1-(第三丁氧基羰基胺基)-2-氟-5-(2-苯基乙基)苯(0.11g)。將此溶解於鹽酸(4mol/L醋酸乙酯溶液,3mL)中,於室溫下攪拌1小時。將反應混合物注入至飽和碳酸氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物以無水硫酸鈉進行乾燥後,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=8/1~5/1)進行精製而得到目標化合物(53mg)。2-fluoro-5-(2-phenylethyl)aniline 1-(t-butoxycarbonylamino)-5-ethynyl-2-fluorobenzene (0.11 g), iodobenzene (0.1 g), A mixture of bis(triphenylphosphine)palladium(0) (16 mg) and copper (I) iodide (5 mg) in N,N-diisopropylamine (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1) to give 1-(t-butoxycarbonylamino)-2-fluoro- 5-Phenylethynylbenzene (0.14 g). This was dissolved in ethyl acetate (3 mL), and 10% palladium carbon powder (50 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 1-(t-butoxycarbonylamino)-2-fluoro-5-(2-phenylethyl)benzene (0.11 g). This was dissolved in hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 8/1 to 5/1) to give the title compound (53 mg).
使用對應的原料物質,依與參考例86相同的方法,得到表11~13記載之參考例87~99的化合物。Using the corresponding starting materials, the compounds of Reference Examples 87 to 99 shown in Tables 11 to 13 were obtained in the same manner as in Reference Example 86.
2-氟-4-甲氧基-5-(2-苯基乙基)苯胺將2-溴-5-氟-4-硝基苯甲醚(0.46g)、苯基乙炔(67mg)、肆(三苯基膦)鈀(0)(38mg)及碘化銅(I)(13mg)之N,N-二異丙基胺(5mL)混合物於室溫下攪拌一夜。將反應混合物以醋酸乙酯進行稀釋,濾除不溶物,將濾液在減壓下進行濃縮。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=10/1~5/1)進行精製而得到5-氟-4-硝基-2-苯基乙基苯甲醚(0.18g)。將此溶解於醋酸乙酯(5mL)中,加入10%鈀碳粉末(0.45g),在氫氣環境下於室溫下攪拌3小時。濾除不溶物,將濾液在減壓下進行濃縮。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=10/1~4/1)進行精製而得到目標化合物(87mg)。2-fluoro-4-methoxy-5-(2-phenylethyl)aniline 2-bromo-5-fluoro-4-nitroanisole (0.46 g), phenylacetylene (67 mg), hydrazine A mixture of (triphenylphosphine)palladium(0) (38 mg) and copper (I) iodide (13 mg) in N,N-diisopropylamine (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1 to 5/1) to give 5-fluoro-4-nitro-2-phenyl. Ethylanisole (0.18 g). This was dissolved in ethyl acetate (5 mL), and 10% palladium carbon powder (0.45 g) was added thereto, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1 to 4/1) to give the title compound (87 mg).
2-氟-5-[2-(2-甲氧基苯基)-1,1-二甲基乙基]苯胺於2-[3-(第三丁氧基羰基胺基)-4-氟苯基]-1-(2-甲氧基苯基)-2-甲基-1-丙烷(0.59g)之四氫呋喃(7.5mL)-水(0.75mL)混合物中,加入氫化硼鈉(0.17g),於室溫下攪拌1小時。將反應混合物以水稀釋,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=4/1)進行精製而得到2-[3-(第三丁氧基羰基胺基)-4-氟苯基]-1-(2-甲氧基苯基)-2-甲基-1-丙烷(0.54g)。將此溶解於乙醇(8mL)-四氫呋喃(3mL)中,加入2mol/L鹽酸(0.2mL)及10%鈀碳粉末(0.27g),在氫氣環境下於室溫下攪拌5小時。於反應混合物中加入碳酸氫鈉,攪拌10分鐘後,濾除不溶物,將濾液在減壓下進行濃縮。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=7/1)進行精製而得到2-[3-(第三丁氧基羰基胺基)-4-氟苯基]-1-(2-甲氧基苯基)-2-甲氧丙烷(0.15g)。於此加入鹽酸(4mol/L醋酸乙酯溶液,3mL),於室溫下攪拌1小時。將反應混合物注入至飽和碳酸氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物以無水硫酸鈉進行乾燥後,將溶媒於減壓下餾除,得到目標化合物(0.11g)。2-fluoro-5-[2-(2-methoxyphenyl)-1,1-dimethylethyl]aniline in 2-[3-(t-butoxycarbonylamino)-4-fluoro Add borohydride sodium (0.17 g) to a mixture of phenyl]-1-(2-methoxyphenyl)-2-methyl-1-propane (0.59 g) in tetrahydrofuran (7.5 mL)-water (0.75 mL). ), stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 4 / 1) to give 2-[3-(t-butoxycarbonylamino)-4. -Fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propane (0.54 g). This was dissolved in ethanol (8 mL)-tetrahydrofuran (3 mL), and 2 mol/L hydrochloric acid (0.2 mL) and 10% palladium carbon powder (0.27 g) were added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. Sodium hydrogencarbonate was added to the reaction mixture, and after stirring for 10 minutes, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 7/1) to give 2-[3-(t-butoxycarbonylamino)-4. -Fluorophenyl]-1-(2-methoxyphenyl)-2-methoxypropane (0.15 g). Hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (0.11 g).
4-氯-3-硝基硫酚在冰冷下,於濃硫酸(30mL)中加入4-氯-3-硝基苯胺(5.18g),於同溫下攪拌5分鐘。在冰冷下於混合物中加入亞硝酸鈉(3.1g)之水(30mL)溶液,升溫至50℃,加入二硫碳酸鉀0-乙基(14.4g)之水(60mL)溶液,於50℃下攪拌1小時。將反應混合物冷卻至室溫,以二乙基醚進行萃取2次。合併萃取物,依序以1mol/L氫氧化鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=7/3)進行精製而得到二硫碳酸O-乙基S-(4-氯-3-硝基苯基)(2.96g)。將此溶解於四氫呋喃(50mL)中,在冰冷下加入至氫化鋁鋰(1.62g)之四氫呋喃(50mL)懸濁液中,於室溫下攪拌10分鐘。將反應混合物冰冷,加入水(1.8mL)、15%氫氧化鈉水溶液(1.8mL)及水(5.4mL),於室溫下攪拌30分鐘。濾除不溶物後,將濾液以醋酸乙酯進行稀釋,依序以1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=9/1~1/9)進行精製而得到目標化合物(1.28g)。4-Chloro-3-nitrothiophenol 4-Chloro-3-nitroaniline (5.18 g) was added to concentrated sulfuric acid (30 mL) under ice-cooling, and stirred at the same temperature for 5 min. Add a solution of sodium nitrite (3.1 g) in water (30 mL) to the mixture under ice-cooling, warm to 50 ° C, and add potassium disulfate 0-ethyl (14.4 g) in water (60 mL) at 50 ° C Stir for 1 hour. The reaction mixture was cooled to room temperature and extracted twice with diethyl ether. The extracts were combined, washed with 1 mol/L sodium hydroxide aqueous solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, and the residue was applied to a cerium oxide gel tube. Column chromatography (extraction solvent: n-hexane ~ n-hexane / ethyl acetate = 7 / 3) was purified to give O-ethyl S-(4-chloro-3-nitrophenyl) disulfate (2.96 g). This was dissolved in tetrahydrofuran (50 mL), and added to a suspension of lithium aluminum hydride (1.62 g) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was ice-cooled, and water (1.8 mL), 15% aqueous sodium hydroxide (1. After the insoluble matter was filtered off, the filtrate was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid, water and brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane/ethyl acetate = 9/1 to 1/9) to give the title compound (1.28 g).
5-苄基硫-2-氯苯胺於4-氯-3-硝基硫酚(0.4g)及溴化苄基(0.3mL)之N,N-二甲基甲醯胺(6mL)溶液中加入碳酸鉀(0.44g),於室溫下攪拌15分鐘。於反應混合物中加入水並以醋酸乙酯進行萃取,將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=9/1)進行精製而得到1-苄基硫-4-氯-3-硝基苯(0.54g)。將此溶解於甲醇(5mL)-四氫呋喃(5mL)中,於冰冷下,加入溴化鎳(II)(21mg)及氫化硼鈉(0.22g),於同溫下攪拌30分鐘、及於室溫下攪拌1小時。將反應混合物以醋酸乙酯進行稀釋,依序以飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(0.38g)。5-Benzylthio-2-chloroaniline in a solution of 4-chloro-3-nitrothiophenol (0.4g) and benzyl bromide (0.3mL) in N,N-dimethylformamide (6mL) Potassium carbonate (0.44 g) was added and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 9/1) to give 1-benzylthio-4-chloro-3-nitro Benzene (0.54 g). This was dissolved in methanol (5 mL)-tetrahydrofuran (5 mL), and then, under ice cooling, nickel (II) bromide (21 mg) and sodium borohydride (0.22 g) were added and stirred at the same temperature for 30 minutes and at room temperature. Stir under 1 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution and water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.38 g).
2-氟-5-巰基苯胺於5-溴-2-氟苯胺(4.15g)、3-巰基丙酸甲酯(2.62g)、4,5-雙(二苯基膦)-9,9-二甲基(0.63g)及N,N-二異丙基乙基胺(5.64g)之1,4-二烷(80mL)混合物中,加入參(二亞苄基丙酮)二鈀(0)(0.3g),於氬氣體環境下加熱迴流一夜。濾除不溶物,將濾液在減壓下進行濃縮。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=20/1~5/1~2/1)進行精製,而得到2-氟-5-(2-甲氧基羰基乙基硫)苯胺(4.62g)。將此溶解於四氫呋喃(120mL)中,於-78℃下加入第三丁氧鉀(1mol/L四氫呋喃溶液,80.6mL),於同溫下攪拌15分鐘。於反應混合物中加入1mol/L鹽酸(81mL),升溫至室溫,攪拌5分鐘。將混合物注入至醋酸乙酯中,使有機層分離。將有機層以飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=4/1)進行精製,而得到目標化合物(1.85g)。2-Fluoro-5-mercaptoaniline in 5-bromo-2-fluoroaniline (4.15 g), methyl 3-mercaptopropionate (2.62 g), 4,5-bis(diphenylphosphino)-9,9- Dimethyl (0.63g) and N,N-diisopropylethylamine (5.64g) of 1,4-two To the mixture of the alkane (80 mL), bis(dibenzylideneacetone)dipalladium(0) (0.3 g) was added, and the mixture was heated to reflux overnight under an argon atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 20/1 to 5/1 to 2/1) to give 2-fluoro-5-(2) -Methoxycarbonylethylthio)aniline (4.62 g). This was dissolved in tetrahydrofuran (120 mL), and potassium tributoxide (1 mol/L tetrahydrofuran solution, 80.6 mL) was added at -78 ° C, and stirred at the same temperature for 15 minutes. 1 mol/L hydrochloric acid (81 mL) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 5 minutes. The mixture was poured into ethyl acetate to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 4 / 1) to give the title compound (1.85 g).
2-氟-6-甲氧苄基醇於2-氟-6-甲氧苯甲醛(0.63g)之四氫呋喃(5mL)溶液中加入水(0.5mL)及氫化硼鈉(0.17g),於室溫下攪拌1小時。將反應混合物以水稀釋,以二乙基醚進行萃取。將萃取物以飽和食鹽水予以洗淨後,將溶媒於減壓下餾除,得到目標化合物(0.58g)。2-Fluoro-6-methoxybenzyl alcohol In a solution of 2-fluoro-6-methoxybenzaldehyde (0.63g) in tetrahydrofuran (5mL), water (0.5mL) and sodium borohydride (0.17g) Stir for 1 hour at room temperature. The reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure to give the title compound (0.58 g).
使用對應的原料物質,依與參考例105相同的方法,得到表14記載之參考例106~107的化合物。Using the corresponding starting materials, the compounds of Reference Examples 106 to 107 shown in Table 14 were obtained in the same manner as in Reference Example 105.
2-氟-6-甲氧苄基溴於2-氟-6-甲氧苄基醇(0.78g)及三乙基胺(0.91mL)之醋酸乙酯(12mL)溶液中,在冰冷下加入甲磺醯氯(0.43mL),於同溫下攪拌30分鐘。濾除不溶物,將不溶液以醋酸乙酯(4mL)洗淨。合併濾液與洗淨液,加入溴化鋰.1水合物(2.62g),於55℃下攪拌2小時。將反應混合物注入水中,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=7/3)進行精製而得到目標化合物(0.82g)。2-Fluoro-6-methoxybenzyl bromide in 2-ethyl-6-methoxybenzyl alcohol (0.78 g) and triethylamine (0.91 mL) in ethyl acetate (12 mL) Methanesulfonium chloride (0.43 mL) was stirred at the same temperature for 30 minutes. The insoluble material was filtered off, and the solution was washed with ethyl acetate (4 mL). Combine the filtrate and the washing solution, and add lithium bromide. 1 hydrate (2.62 g) was stirred at 55 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 7 / 3) to give the title compound (0.82 g).
使用對應的原料物質,依與參考例108相同的方法,得到表14記載之參考例109~110的化合物。Using the corresponding starting materials, the compounds of Reference Examples 109 to 110 shown in Table 14 were obtained in the same manner as in Reference Example 108.
2-(5-氟-2-甲氧苯基)-2-丙醇5-氟-2-甲氧基苯甲醛(1g)之丙酮(4mL)溶液中,於室溫下加入過錳酸鋰(1.54g)之水(16mL)溶液,加熱迴流4小時。將反應混合物冷卻至室溫,加入2mol/L氫氧化鈉水溶液(5.2mL),濾除不溶物。將濾液以醋酸乙酯予以洗淨後,於水層加入2mol/L鹽酸使其呈酸性,以醋酸乙酯進行萃取2次。合併萃取物並以飽和食鹽水洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/1~醋酸乙酯)進行精製而得到5-氟-2-甲氧基苯甲酸(0.66g)。將此溶解於N,N-二甲基甲醯胺(15mL)中,加入碳酸鋰(0.63g)及碘化甲基(0.26mL),於室溫下攪拌2小時。將反應混合物以醋酸乙酯進行稀釋,依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除,得到5-氟-2-甲氧基苯甲酸甲酯(0.7g)。將此溶解於四氫呋喃(10mL)中,在冰冷下加入甲基碘化鎂(3.0mol/L二乙基醚溶液,3.82mL),於室溫下攪拌2小時。於反應混合物中加入飽和氯化銨水溶液,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(0.65g)。Add 2-(5-fluoro-2-methoxyphenyl)-2-propanol 5-fluoro-2-methoxybenzaldehyde (1 g) in acetone (4 mL), add lithium permanganate at room temperature A solution of (1.54 g) in water (16 mL) was heated to reflux for 4 h. The reaction mixture was cooled to room temperature, and a 2 mol/L aqueous sodium hydroxide solution (5.2 mL) was added, and the insoluble matter was filtered out. After the filtrate was washed with ethyl acetate, 2 mol/L hydrochloric acid was added to the aqueous layer to make it acidic, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1 - ethyl acetate) to give 5-fluoro-2-methoxybenzoic acid (0.66). g). This was dissolved in N,N-dimethylformamide (15 mL), and lithium carbonate (0.63 g) and methyl iodide (0.26 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-fluoro-2-methoxybenzene. Methyl formate (0.7 g). This was dissolved in tetrahydrofuran (10 mL), and methyl magnesium iodide (3.0 mol/L diethyl ether solution, 3.82 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.65 g).
使用對應的原料物質,依與參考例111相同的方法,得到表14記載之參考例112~113的化合物。Using the corresponding starting materials, the compounds of Reference Examples 112 to 113 shown in Table 14 were obtained in the same manner as in Reference Example 111.
2-氟-5-(2-氟苄基硫)苯胺2-氟-5-巰基苯胺(0.13g)及2-氟苄基溴(0.12mL)之N,N-二甲基甲醯胺(5mL)溶液中加入碳酸鉀(0.25g),於室溫下攪拌30分鐘。將反應混合物以二乙基醚進行稀釋,依序以水(2次)及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=6/1)進行精製而得到目標化合物(0.17g)。2-Fluoro-5-(2-fluorobenzylthio)aniline 2-fluoro-5-mercaptoaniline (0.13 g) and 2-fluorobenzyl bromide (0.12 mL) of N,N-dimethylformamide Potassium carbonate (0.25 g) was added to the solution of 5 mL), and stirred at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether, washed with water (2 times) and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 6 / 1) to give the title compound (0.17 g).
使用對應的原料物質,依與參考例114相同的方法,得到表15~16記載之參考例115~126的化合物。Using the corresponding starting materials, the compounds of Reference Examples 115 to 126 shown in Tables 15 to 16 were obtained in the same manner as in Reference Example 114.
2-氟-5-(1-甲基-1-苯基乙基硫)苯胺於水(10mL)及濃硫酸(10mL)之混合物中,在室溫下依序加入2-氟-5-巰基苯胺(1.85g)及2-苯基-2-丙醇(1.76g)之四氫呋喃(10mL)溶液,於室溫下攪拌1小時。將反應混合物注入至冰水中,以醋酸乙酯進行萃取。將萃取物依序以水、飽和碳酸氫鈉水溶液及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=6/1~3/1)進行精製而得到目標化合物(1.55g)。2-Fluoro-5-(1-methyl-1-phenylethylthio)aniline in a mixture of water (10 mL) and concentrated sulfuric acid (10 mL), sequentially added 2-fluoro-5-fluorenyl at room temperature A solution of aniline (1.85 g) and 2-phenyl-2-propanol (1.76 g) in tetrahydrofuran (10 mL) was stirred at room temperature for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogencarbonate solution and brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 6/1 to 3/1) to give the title compound (1.55 g).
使用對應的原料物質,依與參考例127相同的方法,得到表16~18記載之參考例128~141的化合物。Using the corresponding starting materials, the compounds of Reference Examples 128 to 141 shown in Tables 16 to 18 were obtained in the same manner as in Reference Example 127.
4-氟-2-甲氧基-5-硝基苯於4-氟-2-甲氧基苯(1.42g)及三乙基胺(1.67mL)之二氯甲烷(20mL)溶液中,在冰冷下加入氯甲酸乙酯(1.05mL),於室溫下攪拌3天。將反應混合物注入至0.5mol/L鹽酸中,以二乙基醚進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。在冰冷下於殘渣中加入濃硫酸(7mL),於同溫度下攪拌15分鐘。在冰冷下,滴下加入發煙硝酸(0.7mL)及濃硫酸(1mL)的混合物,於同溫度下攪拌30分鐘。將反應混合物注入至冰中,於室溫下攪拌30分鐘。將混合物以醋酸乙酯進行萃取,將萃取物依序以水(2次)及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=90/10~67/33)進行精製而得到2-乙氧基羰基氧基-5-氟-4-硝基苯甲醚(0.48g)。於其加入甲醇(8mL)及碳酸氫鈉(0.31g),於室溫下攪拌42小時。將反應混合物注入至0.5mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣懸濁於混合溶媒(洗提溶媒:正己烷/醋酸乙酯=4/1)中並進行濾取,於減壓下進行乾燥而得到目標化合物(0.25g)。4-fluoro-2-methoxy-5-nitrobenzene in a solution of 4-fluoro-2-methoxybenzene (1.42 g) and triethylamine (1.67 mL) in dichloromethane (20 mL) Ethyl chloroformate (1.05 mL) was added under ice cooling, and stirred at room temperature for 3 days. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Concentrated sulfuric acid (7 mL) was added to the residue under ice cooling, and stirred at the same temperature for 15 min. A mixture of fuming nitric acid (0.7 mL) and concentrated sulfuric acid (1 mL) was added dropwise under ice cooling, and stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water (2 times) and brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 90/10 to 67/33) to give 2-ethoxycarbonyloxy-5-fluoro- 4-Nitroanisole (0.48 g). Methanol (8 mL) and sodium hydrogencarbonate (0.31 g) were added thereto, and stirred at room temperature for 42 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent (eluent solvent: n-hexane/ethyl acetate = 4/1), and filtered, and dried under reduced pressure to give the title compound (0.25 g).
使用對應的原料物質,依與參考例142相同的方法,得到表18~19記載之參考例143~147的化合物。Using the corresponding starting materials, the compounds of Reference Examples 143 to 147 shown in Tables 18 to 19 were obtained in the same manner as in Reference Example 142.
2-乙氧基-4-氟-5-硝基苯於4’-氟-2’-羥基苯乙酮(3.08g)、碳酸銫(13.0g)及碘化鈉(0.6g)之N,N-二甲基甲醯胺(20mL)懸濁液中,加入溴化乙烷(2.24mL),於室溫下攪拌一夜。將反應混合物注入至水中,以二乙基醚進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。於殘渣及4,4’-硫雙(6-第三丁基-o-甲酚)(39mg)之二氯甲烷(57.6mL)溶液中,在冰冷下加入3-氯過苯甲酸(4.97g),加熱迴流一夜。將反應混合物冰冷,加入10%亞硫酸鈉水溶液,攪拌20分鐘。將有機層分離,依序以水(3次)、飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣溶解於甲醇(10mL)-四氫呋喃(20mL)中,加入甲氧鈉(28%甲醇溶液,5mL),於室溫下攪拌1小時。將反應混合物注入至0.5mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除,得到2-乙氧基-4-氟苯(3.0g)。使用此取代4-氟-2-甲氧基苯而依與參考例142相同的方法,得到目標化合物。2-ethoxy-4-fluoro-5-nitrobenzene in 4'-fluoro-2'-hydroxyacetophenone (3.08 g), cesium carbonate (13.0 g) and sodium iodide (0.6 g), To a suspension of N-dimethylformamide (20 mL), ethyl bromide (2.24 mL) was added and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To a residue and a solution of 4,4'-thiobis(6-tert-butyl-o-cresol) (39 mg) in dichloromethane (57.6 mL), 3-chloroperbenzoic acid (4.97 g) ), heating and refluxing overnight. The reaction mixture was ice-cooled, a 10% aqueous sodium sulfite solution was added and stirred for 20 min. The organic layer was separated, washed with water (3 times), saturated aqueous sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was dissolved in methanol (10 mL)-THF (20 mL). The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-ethoxy-4-fluorobenzene (3.0 g). The title compound was obtained by the same method as that of Reference Example 142, using this, instead of 4-fluoro-2-methoxybenzene.
使用對應的原料物質,依與參考例20相同的方法,得到表19記載之參考例149的化合物。Using the corresponding starting material, the compound of Reference Example 149 shown in Table 19 was obtained in the same manner as in Reference Example 20.
2-[2-(第三丁氧二甲基矽烷基氧基)乙氧基]苄基醇於2-羥基苄基醇(0.4g)及碳酸鉀(0.67g)之N,N-二甲基甲醯胺(6mL)懸濁液中,加入2-(第三丁基二甲基矽烷基氧基)乙基溴(1.05mL),於室溫下攪拌一夜。將反應混合物以二乙基醚進行稀釋,依序以水、1mol/L氫氧化鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=5/1)進行精製而得到目標化合物(0.32g)。2-[2-(T-butoxydimethyldimethylalkyloxy)ethoxy]benzyl alcohol in 2-hydroxybenzyl alcohol (0.4g) and potassium carbonate (0.67g) N,N-dimethyl To a suspension of carbamide (6 mL), 2-(t-butyldimethylsilyloxy)ethyl bromide (1.05 mL) was added and stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether, washed with water, a 1 mol/L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 5 / 1) to give the title compound (0.32 g).
使用對應的原料物質,依與參考例150相同的方法,得到表19記載之參考例151的化合物。Using the corresponding starting material, the compound of Reference Example 151 described in Table 19 was obtained in the same manner as in Reference Example 150.
2-(第三丁氧二甲基矽烷基氧基甲基)苄基醇於1,2-苯二甲醇(2g)及咪唑(1.13g)之N,N-二甲基甲醯胺(30mL)溶液中,加入第三丁氧二甲基氯矽烷(2.08g),於室溫下攪拌3天。將反應混合物以醋酸乙酯進行稀釋,依序以1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=3/2)進行精製而得到目標化合物(1.46g)。N,N-dimethylformamide (30 mL) of 2-(t-butoxy dimethyl decyloxymethyl)benzyl alcohol in 1,2-benzenedimethanol (2 g) and imidazole (1.13 g) To the solution, third butoxy dimethyl chlorodecane (2.08 g) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to give the title compound ( 1.46 g).
使用對應的原料物質,依與參考例152相同的方法,得到表20記載之參考例153~154的化合物。Using the corresponding starting materials, the compounds of Reference Examples 153 to 154 shown in Table 20 were obtained in the same manner as in Reference Example 152.
2,3-二氟-6-(2-甲氧基乙氧基)苄基醇於2,3-二氟-6-羥基苄甲醛(0.63g)及碳酸鉀(0.83g)之N,N-二甲基甲醯胺(4mL)懸濁液中,加入2-甲氧基乙基溴(0.45mL),於室溫下攪拌3天。將反應混合物注入至水中,以二乙基醚進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=85/15~60/40)進行精製而得到2,3-二氟-6-(2-甲氧基乙氧基)苄甲醛(0.62g)。將此溶解於四氫呋喃(6mL)中,加入水(0.6mL)及氫化硼鈉(0.12g),於室溫下攪拌1小時。將反應混合物以水進行稀釋,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除而得目標化合物(0.61g)。2,3-Difluoro-6-(2-methoxyethoxy)benzyl alcohol in N,N of 2,3-difluoro-6-hydroxybenzylcarbaldehyde (0.63 g) and potassium carbonate (0.83 g) To a suspension of dimethylformamide (4 mL), 2-methoxyethyl bromide (0.45 mL) was added and stirred at room temperature for 3 days. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (extraction solvent: n-hexane / ethyl acetate = 85/15 to 60/40) to obtain 2,3-difluoro-6-(2-A Oxyethoxyethoxy)benzylformaldehyde (0.62 g). This was dissolved in tetrahydrofuran (6 mL), and water (0.6 mL) and sodium borohydride (0.12 g) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.61 g).
使用對應的原料物質,依與參考例155相同的方法,得到表20記載之參考例156~159的化合物。Using the corresponding starting materials, the compounds of Reference Examples 156 to 159 shown in Table 20 were obtained in the same manner as in Reference Example 155.
1-(2,3-二氟-6-甲氧基苯基)-1-環丁醇於3,4-二氟苯甲醚(2.47g)之四氫呋喃(50mL)溶液中,在-78℃下加入正丁基鋰(2.64mol/L正己烷溶液,6.5mL),於室溫下攪拌30分鐘。於反應混合物中加入環丁烷(1g)之四氫呋喃(20mL)溶液,於同溫下攪拌30分鐘。於反應混合物中加入飽和氯化銨水溶液,以二乙基醚進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=5/1)進行精製而得到目標化合物(2.69g)。1-(2,3-Difluoro-6-methoxyphenyl)-1-cyclobutanol in 3,4-difluoroanisole (2.47 g) in tetrahydrofuran (50 mL) at -78 ° C n-Butyllithium (2.64 mol/L n-hexane solution, 6.5 mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. A solution of cyclobutane (1 g) in tetrahydrofuran (20 mL) was added and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 5 / 1) to give the title compound (2.69 g).
2-氯-5-(1-甲基-1-苯基乙氧基)苯胺4-氯-3-硝基苯(0.5g)、三(正丁基)膦(0.72mL)及2-苯基-2-丙醇(0.26g)之四氫呋喃(5mL)溶液中,加入1,1’-偶氮雙(N,N-二甲基甲醯胺)(0.5g),於60℃下攪拌20小時。將反應混合物以二乙基醚進行稀釋,濾除不溶物。將濾液在減壓下進行濃縮,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=10/1)進行精製而得到2-氯-5-(1-甲基-1-苯基乙氧基)-1-硝基苯(0.19g)。將此溶解於四氫呋喃(3.5mL)中,在冰冷下加入甲醇(3.5mL)、溴化鎳(II)(11mg)及氫化硼鈉(0.12g),於同溫下攪拌30分鐘,接著於室溫下攪拌30分鐘。將反應混合物以醋酸乙酯進行稀釋,依序以飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=3/1)進行精製而得到目標化合物(0.14g)。2-Chloro-5-(1-methyl-1-phenylethoxy)aniline 4-chloro-3-nitrobenzene (0.5g), tri(n-butyl)phosphine (0.72mL) and 2-benzene In a solution of benzyl-2-propanol (0.26 g) in tetrahydrofuran (5 mL), 1,1'-azobis(N,N-dimethylformamide) (0.5 g) was added and stirred at 60 ° C 20 hour. The reaction mixture was diluted with diethyl ether and the insoluble material was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 10/1) to give 2-chloro-5. -(1-Methyl-1-phenylethoxy)-1-nitrobenzene (0.19 g). This was dissolved in tetrahydrofuran (3.5 mL), and methanol (3.5 mL), nickel (II) bromide (11 mg) and sodium borohydride (0.12 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, followed by room Stir for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3/1) to give the title compound (0.14 g).
使用對應的原料物質,依與參考例161相同的方法,得到表21記載之參考例162~166的化合物。Using the corresponding starting materials, the compounds of Reference Examples 162 to 166 shown in Table 21 were obtained in the same manner as in Reference Example 161.
使用對應的原料物質,依與參考例13或參考例21相同的方法,得到表22~41記載之參考例167~308的化合物。Using the corresponding starting materials, the compounds of Reference Examples 167 to 308 shown in Tables 22 to 41 were obtained in the same manner as in Reference Example 13 or Reference Example 21.
4-氰基-2-氟-5-(2,3-二氟-6-甲氧基苄基氧基)苯胺使用4-溴-2-氟-5-(2,3-二氟-6-甲氧基苄基氧基)苯胺取代5-溴-2-氟苯胺,依與參考例78相同的方法合成4-溴-2-氟-5-(2,3-二氟-6-甲氧基苄基氧基)-1-(第三丁氧基羰基胺基)苯。將此化合物(0.24g)及氰化銅(I)(90mg)之N-甲基-2-吡咯啶酮(1mL)混合物於外溫220℃下攪拌30分鐘。將反應混合物注入至水中,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=2/1~1/1)進行精製而得到目標化合物(54mg)。4-cyano-2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)phenylamine using 4-bromo-2-fluoro-5-(2,3-difluoro-6 -Methoxybenzyloxy)aniline substituted 5-bromo-2-fluoroaniline, 4-bromo-2-fluoro-5-(2,3-difluoro-6-A was synthesized in the same manner as in Reference Example 78 Oxybenzyloxy)-1-(tritoxycarbonylamino)benzene. A mixture of this compound (0.24 g) and copper (I) (90 mg) N-methyl-2-pyrrolidone (1 mL) was stirred at an external temperature of 220 ° C for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 2 / 1 to 1 / 1) to give the title compound (54 mg).
4-氟-3-(2,3-二氟-6-甲氧基苄基氧基)苯胺將4-氟-3-羥基苯甲酸(0.19g)、2,3-二氟-6-甲氧基苄基溴(0.6g)及碳酸鉀(0.5g)之N,N-二甲基甲醯胺(3mL)懸濁液於室溫下攪拌8小時。將反應混合物注入至水中,以二乙基醚進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣溶解於四氫呋喃(6mL),加入甲醇(3mL)、水(3mL)及氫氧化鋰.1水合物(0.5g),於室溫下攪拌1小時。於反應混合物中加入1mol/L鹽酸(15mL),以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣懸濁於混合溶媒(正己烷/醋酸乙酯=4/1)並進行濾取,於減壓下進行乾燥而得到4-氟-3-(2,3-二氟-6-甲氧基苄基氧基)苯甲酸(0.31g)。將此溶解於1,4-二烷(4mL)中,加入三乙基胺(0.41mL)及二苯基磷醯胺(0.21mL),於室溫下攪拌1小時,並加熱迴流4小時。將反應混合物中加入1mol/L氫氧化鈉水溶液(4mL),於室溫下攪拌1小時。反應混合物注入至飽和碳酸氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=2/1~1/1)進行精製後,於粗製生成物中加入二氯甲烷,濾除不溶物,將濾液的溶媒在減壓下餾除,得到目標化合物(70mg)。4-fluoro-3-(2,3-difluoro-6-methoxybenzyloxy)phenylamine 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methyl A suspension of oxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL), and methanol (3 mL), water (3 mL) and lithium hydroxide were added. 1 hydrate (0.5 g) was stirred at room temperature for 1 hour. 1 mol/L hydrochloric acid (15 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent (hexane/ethyl acetate = 4/1) and filtered, and dried under reduced pressure to give 4-fluoro-3-(2,3-difluoro-6-methoxy (Benzyloxy)benzoic acid (0.31 g). Dissolve this in 1,4-two Triethylamine (0.41 mL) and diphenylphosphoniumamine (0.21 mL) were added to aq. (4 mL), and stirred at room temperature for 1 hour and heated to reflux for 4 hours. A 1 mol/L aqueous sodium hydroxide solution (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane/ethyl acetate = 2/1 to 1/1), and then dichloromethane was added to the crude product to remove insolubles. The solvent of the filtrate was distilled off under reduced pressure to give the title compound (70 mg).
使用對應的原料物質,依與參考例13或參考例21相同的方法,得到表41~43記載之參考例311~321的化合物。Using the corresponding starting material, the compounds of Reference Examples 311-321 described in Tables 41 to 43 were obtained in the same manner as in Reference Example 13 or Reference Example 21.
使用對應的原料物質,依與參考例160相同的方法,得到表43記載之參考例322的化合物。The compound of Reference Example 322 shown in Table 43 was obtained by the same method as Reference Example 160 using the corresponding starting material.
使用對應的原料物質,依與參考例161相同的方法,得到表43記載之參考例323~324的化合物。Using the corresponding starting materials, the compounds of Reference Examples 323 to 324 shown in Table 43 were obtained in the same manner as in Reference Example 161.
2,3-二氟-6-甲氧基苯於2,3-二氯-6-甲氧基苯甲醛(2.58g)之二氯甲烷(45mL)溶液中在冰冷下加入3-氯過苯甲酸(5.97g),加熱迴流一夜。將反應混合物冰冷,加入10%亞硫酸鈉水溶液,攪拌20分鐘。使有機層分離,依序以水(2次)、飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣溶解於四氫呋喃(15mL)-甲醇(7.5mL)中,加入甲氧鈉(28%甲醇溶液,3.75mL),於室溫下攪拌1小時。將反應混合物注入至1mol/L鹽酸中,以醋酸乙酯進行稀釋。將萃取物以飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣依序以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=2/3)及胺基丙基二氧化矽凝膠管柱層析法(洗提溶媒:醋酸乙酯/甲醇=9/1~3/2)進行精製而得到目標化合物(1.7g)。Add 2-chloroperbenzene to a solution of 2,3-difluoro-6-methoxybenzene in 2,3-dichloro-6-methoxybenzaldehyde (2.58 g) in dichloromethane (45 mL) Formic acid (5.97 g) was heated to reflux overnight. The reaction mixture was ice-cooled, a 10% aqueous sodium sulfite solution was added and stirred for 20 min. The organic layer was separated, washed with water (2 times), a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL)-methanol (7.5 mL). The reaction mixture was poured into 1 mol/L hydrochloric acid and diluted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was sequentially subjected to cerium oxide gel column chromatography (eluent solvent: n-hexane to n-hexane/ethyl acetate = 2/3) and aminopropyl cerium oxide gel column chromatography ( The elution solvent: ethyl acetate/methanol = 9/1 to 3/2) was purified to give the title compound (1.7 g).
使用對應的原料物質,依與參考例325相同的方法,得到表43記載之參考例326的化合物。Using the corresponding starting material, the compound of Reference Example 326 described in Table 43 was obtained in the same manner as in Reference Example 325.
2,4-二氟-5-硝基苄基醇於2,4-二氟苯甲醛(2.27g)之二氯甲烷(6mL)溶液中,在冰冷下加入濃硫酸(6mL)攪拌15分鐘。在冰冷下於混合物中加入發煙硝酸(1mL),於同溫下攪拌30分鐘,接著於室溫下攪拌1小時。將反應混合物以醋酸乙酯進行稀釋,加入水,使有機層分離。將有機層依序以飽和碳酸氫鈉水溶液(2次)、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=7/3)進行精製而得到2,4-二氟-5-硝基苯甲醛(2.63g)。將所得之2,4-二氟-5-硝基苯甲醛(1g)溶解於四氫呋喃(15mL)中,在冰冷下加入氫化硼鈉(0.3g),於室溫下攪拌5分鐘。於反應混合物中加入1mol/L鹽酸,以醋酸乙酯進行萃取。將萃取物以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(0.76g)。2,4-Difluoro-5-nitrobenzyl alcohol was added to a solution of 2,4-difluorobenzaldehyde (2.27 g) in dichloromethane (6 mL). To the mixture was added fuming nitric acid (1 mL) under ice-cooling, and stirred at the same temperature for 30 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, water was added and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution (2 times), water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane to n-hexane/ethyl acetate = 7/3) to obtain 2,4-difluoro-5-nitrobenzaldehyde ( 2.63g). The obtained 2,4-difluoro-5-nitrobenzaldehyde (1 g) was dissolved in tetrahydrofuran (15 mL), and sodium borohydride (0.3 g) was added under ice cooling, and the mixture was stirred at room temperature for 5 minutes. 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.76 g).
使用對應的原料物質,依與參考例327相同的方法,得到表43記載之參考例328的化合物。The compound of Reference Example 328 shown in Table 43 was obtained by the same method as Reference Example 327 using the corresponding starting material.
使用2,3-二氟-6-甲氧基苯或2,3-二氟-6-(2甲氧基乙氧基)苯以代替4-氟-3-硝基苯,並使用4-氟-3-硝基苄基醇或2,4-二氟-5-硝基苄基醇或4-氟-2-甲氧基-5-硝基苄基醇以代替1-(2-氟-6-甲氧基苯基)乙醇,依與參考例21相同的方法,得到表44記載之參考例329~331的化合物。Use 2,3-difluoro-6-methoxybenzene or 2,3-difluoro-6-(2-methoxyethoxy)benzene instead of 4-fluoro-3-nitrobenzene and use 4- Instead of 1-(2-fluoro), fluoro-3-nitrobenzyl alcohol or 2,4-difluoro-5-nitrobenzyl alcohol or 4-fluoro-2-methoxy-5-nitrobenzyl alcohol -6-methoxyphenyl)ethanol The compound of Reference Examples 329 to 331 shown in Table 44 was obtained by the same method as that of Reference Example 21.
2,3-二氟-6-(2-甲氧基乙氧基)苯胺於3,4-二氟苯(1.43g)及碳酸銫(4.89g)之N,N-二甲基甲醯胺(10mL)懸濁液中加入2-甲氧基乙基溴(0.94mL),於室溫下攪拌4天。將反應混合物注入至水中,以二乙基醚進行萃取。將萃取物依序以1mol/L氫氧化鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣溶解於四氫呋喃(39mL),於-78℃下加入正丁基鋰(2.64mol/L正己烷溶液,3.25mL),於同溫下攪拌30分鐘。於反應混合物中加入乾冰(10g),於室溫下攪拌30分鐘。於反應混合物中加入2mol/L鹽酸使其呈酸性,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除,得到2,3-二氟-6-(2-甲氧基乙氧基)苯甲酸(1.48g)。將所得之2,3-二氟-6-(2-甲氧基乙氧基)苯甲酸(0.5g)溶解於1,4-二烷(10mL)中,如入三乙基胺(0.45mL)及二苯基磷醯胺(0.61mL),於室溫下攪拌一夜。於反應混合物中加入乙醇(0.99g),加熱迴流5小時。將反應混合物以醋酸乙酯進行稀釋,依序以1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。於殘渣之乙醇(10mL)懸濁液中加入5mol/L氫氧化鈉水溶液(4.3mL),加熱迴流2小時。將反應混合物以醋酸乙酯進行稀釋,依序以水(2次)及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=3/1)進行精製而得到目標化合物(75mg)。N,N-dimethylformamide of 2,3-difluoro-6-(2-methoxyethoxy)aniline in 3,4-difluorobenzene (1.43 g) and cesium carbonate (4.89 g) 2-Methoxyethyl bromide (0.94 mL) was added to a suspension (10 mL), and stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with a 1 mol/L sodium hydroxide aqueous solution, water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (39 mL), and n-butyl lithium (2.64 mol/L n-hexane solution, 3.25 mL) was added at -78 ° C, and the mixture was stirred at the same temperature for 30 minutes. Dry ice (10 g) was added to the reaction mixture, and stirred at room temperature for 30 min. 2 mol/L hydrochloric acid was added to the reaction mixture to make it acidic, and extraction was carried out with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid. (1.48g). The obtained 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (0.5 g) was dissolved in 1,4-two Acetone (10 mL) was added with triethylamine (0.45 mL) and diphenylphosphoniumamine (0.61 mL), and stirred at room temperature overnight. Ethanol (0.99 g) was added to the reaction mixture, and the mixture was heated to reflux for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A 5 mol/L aqueous sodium hydroxide solution (4.3 mL) was added to a suspension of the residue in ethanol (10 mL), and the mixture was refluxed for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water (2 times) and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3 / 1) to give the title compound (75 mg).
使用對應的原料物質,依與參考例332相同的方法,得到表44記載之參考例333的化合物。Using the corresponding starting material, the compound of Reference Example 333 shown in Table 44 was obtained in the same manner as in Reference Example 332.
2-氟-5-[N-(2,6-二氟苯基)-N-甲基胺基]甲基-4-甲氧基苯胺於4-氟-2-甲氧基-5-硝基苄基醇(0.3g)之二氯甲烷(5mL)溶液中,在室溫下加入三乙基胺(0.31mL)及甲磺醯氯(0.14mL),攪拌3小時。將反應混合物以二氯甲烷進行稀釋,以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣溶解於乙腈(2mL)-乙醇(2mL)中,加入觸媒量之碘化鈉及2,6-二氟苯胺(0.45mL),於60℃下攪拌一夜。將反應混合物以醋酸乙酯進行稀釋,以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=2/3)進行精製而得到5-氟-2-[N-(2,6-二氟苯基)胺基]甲基-4-硝基苯甲醚(0.41g)。將此溶解於N,N-二甲基甲醯胺(3mL)中,在冰冷下加入氫化鈉(55%、84mg),於同溫下攪拌5分鐘。於反應混合物中加入碘化甲基(0.096mL),於室溫下攪拌一夜。於反應混合物中加入飽和氯化銨水溶液,以醋酸乙酯進行萃取。將萃取物以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=1/1)進行精製而得到5-氟-2-[N-(2,6-二氟苯基)-N-甲基胺基]甲基-4-硝基苯甲醚(0.17g)。將此溶解於甲醇(3mL)-四氫呋喃(3mL)中,在冰冷下,加入溴化鎳(II)(5mg)及氫化硼鈉(52mg),於同溫下攪拌15分鐘及於室溫下攪拌15分鐘。將反應混合物以醋酸乙酯進行稀釋,依序以飽和碳酸氫鈉水溶液、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷~正己烷/醋酸乙酯=3/2)進行精製而得到目標化合物(0.12g)。2-fluoro-5-[N-(2,6-difluorophenyl)-N-methylamino]methyl-4-methoxyaniline in 4-fluoro-2-methoxy-5-nitrate To a solution of the benzyl alcohol (0.3 g) in dichloromethane (5 mL), triethylamine (0.31 mL) and methanesulfonium chloride (0.14 mL) were added at room temperature and stirred for 3 hours. The reaction mixture was diluted with methylene chloride, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in acetonitrile (2 mL)-ethanol (2 mL), and the mixture of sodium iodide and 2,6-difluoroaniline (0.45 mL) was added and stirred at 60 ° C overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 2/3) to give 5-fluoro-2-[N-(2,6- Difluorophenyl)amino]methyl-4-nitroanisole (0.41 g). This was dissolved in N,N-dimethylformamide (3 mL), and sodium hydride (55%, < Methyl iodide (0.096 mL) was added to the reaction mixture and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 1/1) to give 5-fluoro-2-[N-(2,6- Difluorophenyl)-N-methylamino]methyl-4-nitroanisole (0.17 g). This was dissolved in methanol (3 mL)-tetrahydrofuran (3 mL). Toluene (II) (5 mg) and sodium borohydride (52 mg) were added and the mixture was stirred at room temperature for 15 minutes and stirred at room temperature. 15 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution and water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to give the title compound (0.12 g).
使用對應的原料物質,依與參考例334相同的方法,得到表44記載之參考例335的化合物。Using the corresponding starting material, the compound of Reference Example 335 shown in Table 44 was obtained by the same method as Reference Example 334.
2-氟-5-[N-(2-氟-6-甲氧基苯基)-N-甲基胺基]甲基苯胺於4-氟-3-硝基苯甲酸(1.57g)之二氯甲烷(25mL)溶液中加入N,N-二甲基甲醯胺(0.005mL)及草醯氯(4.32g),於室溫下攪拌1小時後,將反應混合物於減壓下進行濃縮。將殘渣之四氫呋喃(5mL)溶液加入至2-氟-6-甲氧基苯胺(1.2g)及碳酸氫鈉(2.14g)之四氫呋喃(10mL)懸濁液中,於室溫下攪拌一夜。將反應混合物注入至水中,以醋酸乙酯進行萃取。將萃取物依序以1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣懸濁於二氯甲烷並進行濾取,於減壓下進行乾燥,得到4-氟-3-硝基-N-(2-氟-6-甲氧基苯基)苯甲醯胺(1.1g)。將此溶解於N,N-二甲基甲醯胺(12mL)中,在冰冷下加入氫化鈉(55%,172mg)及碘化甲基(0.76g),於室溫下攪拌一夜。將反應混合物注入至水中,以醋酸乙酯進行萃取。將萃取物以水(3次)及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除,得到4-氟-3-硝基-N-(2-氟-6-甲氧基苯基)-N-甲基苯甲醯胺(1.15g)。將所得之4-氟-3-硝基-N-(2-氟-6-甲氧基苯基)-N-甲基苯甲醯胺(0.3g)溶解於甲醇(10mL)-四氫呋喃(10mL),在冰冷下,加入溴化鎳(II)(10mg)及氫化硼鈉(0.11g),於同溫下攪拌30分鐘及於室溫下攪拌30分鐘。將反應混合物注入至飽和碳酸氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除,而得到3-胺基-4-氟-N-(2-氟-6-甲氧基苯基)-N-甲基苯甲醯胺(0.27g)。將此溶解於四氫呋喃(8mL)中,加入硼烷.四氫呋喃錯合物(1mol/L四氫呋喃溶液,3.3mL),加熱迴流2小時。在冰冷下於反應混合物中加入甲醇,攪拌10分鐘。將混合物注入至飽和碳酸氫鈉水溶液中,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=3/1)進行精製而得到目標化合物(0.11g)。2-Fluoro-5-[N-(2-fluoro-6-methoxyphenyl)-N-methylamino]methylaniline in 4-fluoro-3-nitrobenzoic acid (1.57 g) N,N-dimethylformamide (0.005 mL) and grass chloroform (4.32 g) were added to a solution of chloromethane (25 mL), and the mixture was stirred at room temperature for 1 hr. A solution of the residue in tetrahydrofuran (5 mL) was added to a suspension of 2-fluoro-6-methoxyaniline (1.2 g) and sodium hydrogencarbonate (2.14 g) in tetrahydrofuran (10 mL) and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane and filtered, and dried under reduced pressure to give 4-fluoro-3-nitro-N-(2-fluoro-6-methoxyphenyl) benzamide ( 1.1g). This was dissolved in N,N-dimethylformamide (12 mL), and sodium hydride (55%, EtOAc) The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water (3 times) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-fluoro-3-nitro-N-(2-fluoro -6-Methoxyphenyl)-N-methylbenzamide (1.15 g). The obtained 4-fluoro-3-nitro-N-(2-fluoro-6-methoxyphenyl)-N-methylbenzamide (0.3 g) was dissolved in methanol (10 mL)-tetrahydrofuran (10 mL) Under ice cooling, nickel (II) bromide (10 mg) and sodium borohydride (0.11 g) were added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3-amino-4-fluoro-N-(2-fluoro-6- Methoxyphenyl)-N-methylbenzamide (0.27 g). This was dissolved in tetrahydrofuran (8 mL) and borane was added. Tetrahydrofuran complex (1 mol/L tetrahydrofuran solution, 3.3 mL) was heated under reflux for 2 hours. Methanol was added to the reaction mixture under ice cooling and stirred for 10 minutes. The mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3/1) to give the title compound (0.11 g).
使用對應的原料物質,依與參考例336相同的方法,得到表45記載之參考例337~340的化合物。Using the corresponding starting materials, the compounds of Reference Examples 337 to 340 shown in Table 45 were obtained in the same manner as in Reference Example 336.
使用對應的原料物質,依與參考例325相同的方法,得到表45記載之參考例341~342的化合物。Using the corresponding starting materials, the compounds of Reference Examples 341 to 342 shown in Table 45 were obtained in the same manner as in Reference Example 325.
使用2,3-二氟-6-(2-乙氧基乙氧基)苯或2,3-二氟-6-[2-(第三丁基二甲基矽烷基氧基)乙氧基]苯以代替4-氟-3-硝基苯,使用4-氟-3-硝基苄基醇以代替1-(2-氟-6-甲氧基苯基)乙醇,依與參考例21相同的方法,得到表45記載之參考例343~344的化合物。Use 2,3-difluoro-6-(2-ethoxyethoxy)benzene or 2,3-difluoro-6-[2-(t-butyldimethylmethylalkyloxy)ethoxy Benzene instead of 4-fluoro-3-nitrobenzene, 4-fluoro-3-nitrobenzyl alcohol instead of 1-(2-fluoro-6-methoxyphenyl)ethanol, according to Reference Example 21 In the same manner, the compounds of Reference Examples 343 to 344 shown in Table 45 were obtained.
4-氟-3-硝基-2-甲氧基苯甲酸在冰冷下於4-氟-2-甲氧基苯甲酸(0.96g)中加入濃硫酸(6mL)並攪拌15分鐘。在冰冷下於混合物中加入濃硫酸(0.6mL),於同溫下攪拌1小時。於反應混合物中加入冰,於室溫下攪拌10分鐘後,以醋酸乙酯進行萃取。將萃取物以水(2次)及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。於殘渣中加入混合溶媒(正己烷/醋酸乙酯=2/1),濾取不溶物,於減壓下進行乾燥而得到目標化合物(0.78g)。4-Fluoro-3-nitro-2-methoxybenzoic acid To a solution of 4-fluoro-2-methoxybenzoic acid (0.96 g) was added concentrated sulfuric acid (6 mL) and stirred for 15 min. Concentrated sulfuric acid (0.6 mL) was added to the mixture under ice cooling, and stirred at the same temperature for one hour. Ice was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes and then extracted with ethyl acetate. The extract was washed with water (2 times) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A mixed solvent (n-hexane/ethyl acetate = 2/1) was added to the residue, and the insoluble material was filtered, and dried under reduced pressure to give the title compound (0.78 g).
使用對應的原料物質,依與參考例336相同的方法,得到表46記載之參考例346的化合物。Using the corresponding starting material, the compound of Reference Example 346 shown in Table 46 was obtained in the same manner as in Reference Example 336.
5-甲氧基羰基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於4-胺基噻吩-2,3-二羧酸二甲基鹽酸鹽(0.5g)及三乙基胺(0.84mL)之四氫呋喃(10mL)懸濁液中加入三光氣(0.41g)之四氫呋喃(5mL)溶液,在60℃下攪拌1小時。濾除不溶物,將濾液於減壓下進行濃縮。將殘渣溶解於四氫呋喃(8mL)中,加入2-氯-5-(3,4-二氫喹啉-1(2H)-基磺醯基)苯胺(0.64g)及4-二甲基胺基吡啶(0.49g)之四氫呋喃(8mL)溶液,於60℃下攪拌2小時。將反應混合物以醋酸乙酯進行稀釋,依序以1mol/L鹽酸及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣溶解於甲醇(15mL)。於此溶液中加入甲氧鈉(28%甲醇溶液,1.15mL),於室溫下攪拌10分鐘。將反應混合物以醋酸乙酯進行稀釋,依序以1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(0.65g)。5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2 , 4(1H,3H)-dione was suspended in tetrahydrofuran (10 mL) of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.5 g) and triethylamine (0.84 mL). A solution of triphosgene (0.41 g) in tetrahydrofuran (5 mL) was added to the mixture and stirred at 60 ° C for one hour. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL), and 2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)aniline (0.64 g) and 4-dimethylamino group were added. A solution of pyridine (0.49 g) in tetrahydrofuran (8 mL) was stirred at 60 ° C for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (15 mL). Sodium methoxide (28% methanol solution, 1.15 mL) was added to this solution and stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.65 g).
使用對應的原料物質,依與實施例1相同的方法,得到表47~49記載之實施例2~21的化合物。其中,於實施例6的情況下,使用乙醇以取代甲醇,使用乙氧鈉以取代甲氧鈉。Using the corresponding starting materials, the compounds of Examples 2 to 21 shown in Tables 47 to 49 were obtained in the same manner as in Example 1. Here, in the case of Example 6, ethanol was used instead of methanol, and sodium oxyacetate was used instead of sodium methoxide.
5-羧基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-甲氧基羰基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(0.2g)之甲醇(12mL)-四氫呋喃(4mL)溶液中加入氫氧化鋰.1水合物(0.16g),於60℃下攪拌一夜。於反應混合物中加入1mol/L鹽酸,濾取析出之結晶,以水洗淨後於減壓下進行乾燥,得到目標化合物(0.18g)。5-carboxy-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2,4 ( 1H,3H)-dione in 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3 , 4-d]pyrimidine-2,4(1H,3H)-dione (0.2g) in methanol (12mL) - tetrahydrofuran (4mL) solution was added lithium hydroxide. 1 hydrate (0.16 g) was stirred at 60 ° C overnight. 1 mol/L hydrochloric acid was added to the reaction mixture, and the crystals which precipitated were collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.18 g).
使用對應的原料物質,依與實施例1及實施例22相同的方法,得到表50~51記載之實施例23~29的化合物。Using the corresponding starting materials, the compounds of Examples 23 to 29 shown in Tables 50 to 51 were obtained in the same manner as in Example 1 and Example 22.
5-胺甲醯基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-羧基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(14mg)之四氫呋喃(1mL)溶液中加入1,1’-羰基雙-1H-咪唑(9mg),於室溫下攪拌1小時。於反應混合物中加入28%氨水(0.5mL),於室溫下攪拌1小時。將反應混合物以醋酸乙酯進行稀釋,依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:二氯甲烷/甲醇=10/1)進行精製而得到目標化合物(13mg)。5-Aminomethylmercapto-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2 , 4(1H,3H)-dione in 5-carboxy-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3 ,1,4-'-carbonylbis-1H-imidazole (9 mg) was added to a solution of 4-pyrimidine-2,4(1H,3H)-dione (14 mg) in tetrahydrofuran (1 mL). hour. To the reaction mixture was added 28% aqueous ammonia (0.5 mL), and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: methylene chloride / methanol = 10/1) to give the title compound (13 mg).
5-甲基胺甲醯基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮使用對應的原料物質,依與實施例30相同的方法,得到目標化合物。5-methylamine-mercapto-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine -2,4(1H,3H)-dione The target compound was obtained by the same method as Example 30 using the corresponding raw material.
5-(1-羥基-1-甲基乙基)-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-甲氧基羰基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(0.1g)之四氫呋喃(10mL)溶液中在冰冷下加入甲基碘化鎂(3mol/L二乙基醚溶液,0.19mL),於室溫下攪拌一夜。於反應混合物中加入飽和氯化銨水溶液,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(85mg)。5-(1-hydroxy-1-methylethyl)-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3 ,4-d]pyrimidine-2,4(1H,3H)-dione in 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)- Add methyl magnesium iodide (Isopropyl) phenyl] thiophene [3,4-d] pyrimidine-2,4(1H,3H)-dione (0.1 g) in tetrahydrofuran (10 mL) 3 mol/L diethyl ether solution, 0.19 mL), and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (85 mg).
5-羥基甲基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-甲氧基羰基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(0.2g)之四氫呋喃(4mL)溶液中,在冰冷下加入氫化二異丁基鋁(1.01mol/L甲苯溶液,1.5mL)並攪拌1小時。於反應混合物中加入醋酸乙酯並攪拌10分鐘後,加入1mol/L鹽酸,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(0.11g)。5-hydroxymethyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2, 4(1H,3H)-dione in 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene A solution of [3,4-d]pyrimidine-2,4(1H,3H)-dione (0.2 g) in tetrahydrofuran (4 mL) was added with diisobutylaluminum hydride (1.01 mol/L in toluene) under ice cooling. 1.5 mL) and stirred for 1 hour. Ethyl acetate was added to the reaction mixture and stirred for 10 minutes, then 1 mol/L hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.11 g).
5-甲醯基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-羥基甲基-3-[2-氯-5-(3,4-二羥喹啉-1(2H)-基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(77mg)之N,N-二甲基甲醯胺(2.1mL)溶液中加入二氧化錳(IV)(0.77g),於室溫下攪拌一夜。將反應混合物以醋酸乙酯進行稀釋,濾除不溶物。將濾液依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/1)進行精製而得到目標化合物(32mg)。5-Mercapto-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2, 4(1H,3H)-dione in 5-hydroxymethyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [ Manganese (IV) (0.77 g) was added to a solution of 3,4-d]pyrimidine-2,4(1H,3H)-dione (77 mg) in N,N-dimethylformamide (2.1 mL). Stir at room temperature overnight. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered. The filtrate was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (32 mg).
5-甲氧基羰基-3-{2-氟-5-[1-(2-氟-6-甲氧基苯基)乙氧基]苯基}噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於4-胺基噻吩-2,3-二羧酸二甲基鹽酸鹽(90mg)及三乙基胺(0.15mL)之四氫呋喃(3mL)混合物中加入三光氣(74mg)之四氫呋喃(3mL)溶液,於60℃下攪拌30分鐘。濾除不溶物,將濾液於減壓下進行濃縮。將殘渣溶解於四氫呋喃(3mL)中,加入至2-氟-5-[1-(2-氟-6-甲氧基苯基)乙氧基]苯胺(0.1g)及4-二甲氧胺基吡啶(88mg)之四氫呋喃(3mL)溶液中,在60℃下攪拌一夜。於反應混合物中加入1mol/L鹽酸並以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣溶解於甲醇(5mL)中。於此溶液中加入甲氧鈉(28%甲醇溶液,0.21mL),於室溫下攪拌15分鐘。於反應混合物中加入1mol/L鹽酸,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥。將溶媒於減壓下餾除,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/2)進行精製而得到目標化合物(0.14g)。5-methoxycarbonyl-3-{2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenyl}thiophene [3,4-d]pyrimidine-2 , 4(1H,3H)-dione was added to a mixture of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (90 mg) and triethylamine (0.15 mL) in tetrahydrofuran (3 mL) A solution of triphosgene (74 mg) in tetrahydrofuran (3 mL) was stirred at 60 ° C for 30 min. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL) and added to 2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenylamine (0.1 g) and 4-dimethoxyamine A solution of the pyridine (88 mg) in tetrahydrofuran (3 mL) was stirred at 60 ° C overnight. 1 mol/L hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in methanol (5 mL). Sodium methoxide (28% methanol solution, 0.21 mL) was added to this solution and stirred at room temperature for 15 min. 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/2) to give the title compound (0.14 g).
使用對應的原料物質,依與實施例35相同的方法,得到表52~53記載之實施例36~47的化合物。Using the corresponding starting materials, the compounds of Examples 36 to 47 shown in Tables 52 to 53 were obtained in the same manner as in Example 35.
5-羧基-3-{2-氟-5-[1-(2-氟-6-甲氧基苯基)乙氧基]苯基}噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-甲氧基羰基-3-{2-氟-5-[1-(2-氟-6-甲氧基苯基)乙氧基]苯基}噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(0.12g)及甲醇(3mL)之混合物中加入氫氧化鋰.1水合物(99mg),於50℃攪拌1小時。於反應混合物中加入1mol/L鹽酸使其呈酸性,濾取析出之結晶,以水洗淨後於減壓下進行乾燥,得到目標化合物(0.11g)。5-carboxy-3-{2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenyl}thiophene [3,4-d]pyrimidine-2,4 ( 1H,3H)-dione in 5-methoxycarbonyl-3-{2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenyl}thiophene [3 Add lithium hydroxide to a mixture of 4-d]pyrimidine-2,4(1H,3H)-dione (0.12g) and methanol (3mL). 1 hydrate (99 mg) was stirred at 50 ° C for 1 hour. To the reaction mixture, 1 mol/L hydrochloric acid was added to make it acidic, and the crystals which precipitated were collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.11 g).
使用對應的原料物質,依與實施例48相同的方法,得到表53~55記載之實施例49~60的化合物。Using the corresponding starting materials, the compounds of Examples 49 to 60 shown in Tables 53 to 55 were obtained in the same manner as in Example 48.
使用對應的原料物質,依與實施例35相同的方法,得到表55記載之實施例61~65的化合物。Using the corresponding starting materials, the compounds of Examples 61 to 65 shown in Table 55 were obtained in the same manner as in Example 35.
使用對應的原料物質,依與實施例48或實施例93相同的方法,得到表55~56記載之實施例66~70的化合物。Using the corresponding starting materials, the compounds of Examples 66 to 70 shown in Tables 55 to 56 were obtained in the same manner as in Example 48 or Example 93.
使用對應的原料物質,依與實施例35相同的方法,得到表56記載之實施例71的化合物。The compound of Example 71 shown in Table 56 was obtained by the same method as Example 35 using the corresponding material.
5-甲氧基羰基-3-[3-(1-苯基乙基亞磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-甲氧基羰基-3-[3-(1-苯基乙基硫)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(50mg)之丙酮(3mL)-水(0.6mL)溶液中加入碳酸氫鈉(24mg)及OXONE(註冊商標)(84mg),於室溫下攪拌30分鐘。將反應混合物以醋酸乙酯進行萃取,將萃取物依序以1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣懸濁於甲醇後,進行濾取,於減壓下進行乾燥,得到目標化合物(45mg)。5-methoxycarbonyl-3-[3-(1-phenylethylsulfinyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione in 5 -methoxycarbonyl-3-[3-(1-phenylethylsulfanyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (50 mg) in acetone (50 mg) Sodium hydrogencarbonate (24 mg) and OXONE (registered trademark) (84 mg) were added to a solution of water (0.6 mL), and stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1 mol/L hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in methanol, filtered, and dried under reduced pressure to give the title compound (45 mg).
5-甲氧基羰基-3-[3-(1-苯基乙基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-甲氧基羰基-3-[3-(1-苯基乙基硫)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(50mg)之丙酮(3mL)-水(0.6mL)溶液中加入碳酸氫鈉(77mg)及OXONE(註冊商標)(0.28g),於室溫下攪拌30分鐘。將反應混合物以醋酸乙酯進行萃取,將萃取物依序以1mol/L鹽酸、水及飽和食鹽水予以洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣懸濁於甲醇後,進行濾取,於減壓下進行乾燥,得到目標化合物(48mg)。5-methoxycarbonyl-3-[3-(1-phenylethylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione at 5- Methoxycarbonyl-3-[3-(1-phenylethylsulfanyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (50 mg) in acetone (3 mL) To the solution of water (0.6 mL), sodium hydrogencarbonate (77 mg) and OXONE (registered trademark) (0.28 g) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1 mol/L hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in methanol, filtered, and dried under reduced pressure to give the title compound (48 mg).
使用對應的原料物質,依與實施例35相同的方法,得到表56~57記載之實施例74~76的化合物。Using the corresponding starting materials, the compounds of Examples 74 to 76 shown in Tables 56 to 57 were obtained in the same manner as in Example 35.
使用對應的原料物質,依與實施例73相同的方法,得到表57記載之實施例77的化合物。The compound of Example 77 shown in Table 57 was obtained by the same method as Example 73 using the corresponding material.
使用對應的原料物質,依與實施例35相同的方法,得到表57記載之實施例78的化合物。The compound of Example 78 shown in Table 57 was obtained by the same method as Example 35 using the corresponding material.
使用對應的原料物質,依與實施例48相同的方法,得到表57記載之實施例79~82的化合物。Using the corresponding starting materials, the compounds of Examples 79 to 82 shown in Table 57 were obtained in the same manner as in Example 48.
使用對應的原料物質,依與實施例73及實施例48相同的方法,得到表58記載之實施例83的化合物。The compound of Example 83 shown in Table 58 was obtained in the same manner as in Example 73 and Example 48 using the corresponding material.
使用對應的原料物質,依與實施例48相同的方法,得到表58記載之實施例84~87的化合物。Using the corresponding starting materials, the compounds of Examples 84 to 87 shown in Table 58 were obtained in the same manner as in Example 48.
使用對應的原料物質,依與實施例73及實施例48相同的方法,得到表58記載之實施例88的化合物。The compound of Example 88 shown in Table 58 was obtained in the same manner as in Example 73 and Example 48 using the corresponding material.
使用對應的原料物質,依與實施例35相同的方法,得到表58~59記載之實施例89~92的化合物。Using the corresponding starting materials, the compounds of Examples 89 to 92 shown in Tables 58 to 59 were obtained in the same manner as in Example 35.
5-羧基-3-[2-氟-5-(N-甲基-N-苯基胺甲醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-甲氧基羰基-3-[2-氟-5-(N-甲基-N-苯基胺甲醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(0.18g)及氫氧化鋰.1水合物(0.17g)之四氫呋喃(6mL)-甲醇(3mL)-水(3mL)混合物於室溫下攪拌2小時。將反應混合物注入至1mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:二氯甲烷/甲醇=8/1)進行精製而得到目標化合物(0.12g)。5-carboxy-3-[2-fluoro-5-(N-methyl-N-phenylamine-methane)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)- Diketone in 5-methoxycarbonyl-3-[2-fluoro-5-(N-methyl-N-phenylaminecarbamimidyl)phenyl]thiophene [3,4-d]pyrimidine-2,4 (1H,3H)-dione (0.18g) and lithium hydroxide. A mixture of 1 hydrate (0.17 g) in THF (3 mL)-MeOH (3 mL) The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: methylene chloride / methanol = 8 / 1) to give the title compound (0.12 g).
使用對應的原料物質,依與實施例35及實施例93相同的方法,得到表59記載之實施例94的化合物。The compound of Example 94 shown in Table 59 was obtained by the same method as Example 35 and Example 93 using the corresponding raw material.
使用對應的原料物質,依與實施例93相同的方法,得到表59記載之實施例95~97的化合物。Using the corresponding starting materials, the compounds of Examples 95 to 97 shown in Table 59 were obtained in the same manner as in Example 93.
使用對應的原料物質,依與實施例35相同的方法,得到表59~60記載之實施例98~100的化合物。Using the corresponding starting materials, the compounds of Examples 98 to 100 shown in Tables 59 to 60 were obtained in the same manner as in Example 35.
使用對應的原料物質,依與實施例48相同的方法,得到表60記載之實施例101~103的化合物。Using the corresponding starting materials, the compounds of Examples 101 to 103 shown in Table 60 were obtained in the same manner as in Example 48.
使用對應的原料物質,依與實施例1相同的方法,得到表61記載之實施例104~108的化合物。Using the corresponding starting materials, the compounds of Examples 104 to 108 shown in Table 61 were obtained in the same manner as in Example 1.
使用對應的原料物質,依與實施例1及實施例48或實施例93相同的方法,得到表61~74記載之實施例109~201的化合物。Using the corresponding starting materials, the compounds of Examples 109 to 201 shown in Tables 61 to 74 were obtained in the same manner as in Example 1 and Example 48 or Example 93.
5-羧基-3-[2-氟-5-(1-甲基-1-苯基乙基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮將使用2-氟-5-(1-甲基-1-苯基乙基硫)苯胺代替2-氟-5-[1-(2-氟-6-甲氧基苯基)乙氧基]苯基,並依與實施例35相同之方法所得到5-甲氧基羰基-3-[2-氟-5-(1-甲基-1-苯基乙基硫)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(0.1g),溶解於二氯甲烷(2mL)中,加入3-氯過苯甲酸(92mg),於室溫下攪拌一夜。將反應混合物注入至水中,加入1mol/L硫代硫酸鈉水溶液,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鎂進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/1~1/2)進行精製而得到5-甲氧基羰基-3-[2-氟-5-(1-甲基-1-苯基乙基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(0.1g)。使用所得之5-甲氧基羰基-3-[2-氟-5-(1-甲基-1-苯基乙基磺醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮取代5-甲氧基羰基-3-[2-氟-5-(N-甲基-N-苯基胺甲醯基)苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮,依與實施例93相同之方法得到目標化合物。5-carboxy-3-[2-fluoro-5-(1-methyl-1-phenylethylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H) -Diketone will use 2-fluoro-5-(1-methyl-1-phenylethylthio)aniline instead of 2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl) Oxy]phenyl group, and 5-methoxycarbonyl-3-[2-fluoro-5-(1-methyl-1-phenylethylsulfanylphenyl) was obtained in the same manner as in Example 35. Thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (0.1g), dissolved in dichloromethane (2mL), 3-chloroperbenzoic acid (92mg) Stir under night. The reaction mixture was poured into water, and a 1 mol/L aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/1 to 1/2) to give 5-methoxycarbonyl-3-[2-fluoro 5-(1-Methyl-1-phenylethylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (0.1 g). Using the obtained 5-methoxycarbonyl-3-[2-fluoro-5-(1-methyl-1-phenylethylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2, 4(1H,3H)-dione substituted 5-methoxycarbonyl-3-[2-fluoro-5-(N-methyl-N-phenylaminecarbamimidyl)phenyl]thiophene [3,4- d] Pyrimidine-2,4(1H,3H)-dione, the title compound was obtained in the same manner as Example 93.
使用對應的原料物質,依與實施例202相同的方法,得到表75~79記載之實施例203~232的化合物。Using the corresponding starting materials, the compounds of Examples 203 to 232 shown in Tables 75 to 79 were obtained in the same manner as in Example 202.
5-羧基-3-[2-氟-5-(2,3-二氟-6-甲氧基苄基氧基)-4-甲氧基苯基]噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於4-胺基噻吩-2,3-二羧酸二甲基鹽酸鹽(0.13g)及三乙基胺(0.21mL)之四氫呋喃(5mL)懸濁液中,在冰冷下加入三光氣(99mg),於60℃下攪拌30分鐘。將反應混合物以醋酸乙酯進行稀釋,濾除不溶物,將濾液於減壓下進行濃縮。將殘渣溶解於四氫呋喃(4mL)中,加入至2-氟-5-(2,3-二氟-6-甲氧基苄基氧基)-4-甲氧基苯胺(0.16g)及4-二甲基胺基吡啶(0.12g)之四氫呋喃(4mL)溶液中,於60℃下攪拌3天。將反應混合物通至IST公司製ISO ROUTE SCX,以醋酸乙酯使其溶出。將溶出液於減壓下濃縮後,將殘渣溶解於甲醇(5mL),加入甲氧鈉(28%甲醇溶液,0.29mL),於室溫下攪拌30分鐘。於反應混合物中加入1mol/L鹽酸,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣及氫氧化鋰.1水合物(0.21g)之四氫呋喃(4mL)-甲醇(2mL)-水(2mL)混合物於室溫下攪拌30分鐘。將反應混合物注入至1mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/2~醋酸乙酯)進行精製而得到目標化合物(0.13g)。5-carboxy-3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]thiophene [3,4-d]pyrimidine- 2,4(1H,3H)-dione was suspended in tetrahydrofuran (5 mL) of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.13 g) and triethylamine (0.21 mL) In the turbid liquid, triphosgene (99 mg) was added under ice cooling, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL) and added to 2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.16 g) and 4- A solution of dimethylaminopyridine (0.12 g) in tetrahydrofuran (4 mL) was stirred at 60 ° C for 3 days. The reaction mixture was passed to ISO ROUTE SCX manufactured by IST Corporation, and eluted with ethyl acetate. After the eluate was concentrated under reduced pressure, the residue was dissolved in methanol (5 mL), and sodium sulfate (28% methanol solution, 0.29 mL) was added and the mixture was stirred at room temperature for 30 minutes. 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue and lithium hydroxide. A mixture of 1 hydrate (0.21 g) in tetrahydrofuran (4 mL)-MeOH (2 mL) The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/2 - ethyl acetate) to give the title compound (0.13 g).
使用對應的原料物質,依與實施例233相同的方法,得到表79~102記載之實施例234~391的化合物。Using the corresponding starting materials, the compounds of Examples 234 to 391 shown in Tables 79 to 102 were obtained in the same manner as in Example 233.
使用對應的原料物質,依與實施例35及實施例33相同的方法,得到表102記載之實施例392的化合物。The compound of Example 392 shown in Table 102 was obtained by the same method as Example 35 and Example 33 using the corresponding raw material.
使用對應的原料物質,依與實施例30相同的方法,得到表102記載之實施例393~395的化合物。Using the corresponding starting materials, the compounds of Examples 393 to 395 shown in Table 102 were obtained in the same manner as in Example 30.
5-羧基-3-{2-氟-5-[2,3-二氟-6-(2-羥基乙氧基)苄基氧基]苯基}噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於4-胺基噻吩-2,3-二羧酸二甲基鹽酸鹽(0.11g)及三乙基胺(0.19mL)之四氫呋喃(5mL)懸濁液中,在冰冷下加入三光氣(84mg),於60℃下攪拌30分鐘。將反應混合物以醋酸乙酯進行稀釋,濾除不溶物,將濾液於減壓下進行濃縮。將殘渣溶解於四氫呋喃(4mL)中,加入至2-氟-5-{2,3-二氟-6-[2-(第三丁基二甲基矽烷基氧基)乙氧基]苄基氧基}苯胺(0.17g)及4-二甲基胺基吡啶(99mg)之四氫呋喃(4mL)溶液中,於60℃下攪拌一夜。將反應混合物通至IST公司製ISO ROUTE SCX,以醋酸乙酯使其溶出。將溶出液於減壓下濃縮後,將殘渣溶解於甲醇(4mL),加入甲氧鈉(28%甲醇溶液,0.23mL),於室溫下攪拌30分鐘。於反應混合物中加入1mol/L鹽酸,以醋酸乙酯進行萃取。將萃取物以飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣溶解於四氫呋喃(4mL)中,加入四(正丁基)氟化銨(1mol/L四氫呋喃溶液,1.2mL),於室溫下攪拌3小時。將反應混合物注入至1mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣及氫氧化鋰.1水合物(0.17g)之四氫呋喃(5mL)-甲醇(2.5mL)-水(2.5mL)混合物於室溫下攪拌30分鐘。於反應混合物中加入1mol/L鹽酸,以醋酸乙酯進行萃取。將萃取物依序以水及飽和食鹽水予以洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:醋酸乙酯)進行精製而得到目標化合物(0.13g)。5-carboxy-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy]phenyl}thiophene [3,4-d]pyrimidine-2 , 4(1H,3H)-dione was suspended in tetrahydrofuran (5 mL) of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.11 g) and triethylamine (0.19 mL) In the solution, triphosgene (84 mg) was added under ice cooling, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL) and added to 2-fluoro-5-{2,3-difluoro-6-[2-(t-butyldimethylmethylsulfanyloxy)ethoxy]benzyl A solution of oxy}aniline (0.17 g) and 4-dimethylaminopyridine (99 mg) in tetrahydrofuran (4 mL) was stirred at 60 ° C overnight. The reaction mixture was passed to ISO ROUTE SCX manufactured by IST Corporation, and eluted with ethyl acetate. After the eluate was concentrated under reduced pressure, the residue was dissolved in methanol (4 mL), and sodium sulfate (28% methanol solution, 0.23 mL) was added and the mixture was stirred at room temperature for 30 minutes. 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL), and tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 1.2 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue and lithium hydroxide. A mixture of 1 hydrate (0.17 g) in tetrahydrofuran (5 mL)-methanol (2.5 mL) 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: ethyl acetate) to give the title compound (0.13 g).
使用對應的原料物質,依與實施例396相同的方法,得到表102~104記載之實施例397~410的化合物。Using the corresponding starting materials, the compounds of Examples 397 to 410 shown in Tables 102 to 104 were obtained in the same manner as in Example 396.
使用對應的原料物質,依與實施例233相同的方法,得到表104~105記載之實施例411~416的化合物。Using the corresponding starting materials, the compounds of Examples 411 to 416 shown in Tables 104 to 105 were obtained in the same manner as in Example 233.
5-乙氧基羰基-3-{2-氟-5-[2,3-二氟-6-(2-羥基乙氧基)苄基氧基]苯基}噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-羧基-3-{2-氟-5-[2,3-二氟-6-(2-羥基乙氧基)苄基氧基]苯基}噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(0.65g)之乙醇(10mL)-四氫呋喃(5mL)懸濁液中加入對甲苯磺酸.1水合物(24mg),於外溫90℃下攪拌一夜。將反應混合物於減壓下進行濃縮,將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/2~1/4)進行精製而得到目標化合物(0.39g)。5-ethoxycarbonyl-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy]phenyl}thiophene [3,4-d] Pyrimidine-2,4(1H,3H)-dione in 5-carboxy-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy] Add p-toluenesulfonic acid to a suspension of phenyl}thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (0.65 g) in ethanol (10 mL)-tetrahydrofuran (5 mL). The hydrate (24 mg) was stirred overnight at an external temperature of 90 °C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/2 to 1/4) to give the title compound ( 0.39g).
5-乙氧基羰氧-3-(5-{6-[2-(乙氧基羰基氧基)乙氧基]-2,3-二氟苄基氧基}-2-氟苯基)噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮於5-乙氧基羰基-3-{2-氟-5-[2,3-二氟-6-(2-羥基乙氧基)苄基氧基]苯基}噻吩[3,4-d]嘧啶-2,4(1H,3H)-二酮(80mg)之醋酸乙酯(2mL)懸濁液中加入吡啶(0.036mL)及氯甲酸乙酯(0.021mL),於室溫下攪拌一夜。將反應混合物注入至1mol/L鹽酸中,以醋酸乙酯進行萃取。將萃取物以水及飽和食鹽水洗淨後,以無水硫酸鈉進行乾燥,將溶媒於減壓下餾除。將殘渣以二氧化矽凝膠管柱層析法(洗提溶媒:正己烷/醋酸乙酯=1/2)進行精製而得到目標化合物(38mg)。5-ethoxycarbonyloxy-3-(5-{6-[2-(ethoxycarbonyloxy)ethoxy]-2,3-difluorobenzyloxy}-2-fluorophenyl) Thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione in 5-ethoxycarbonyl-3-{2-fluoro-5-[2,3-difluoro-6-(2 -Hydroxyethoxy)benzyloxy]phenyl}thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (80 mg) in ethyl acetate (2 mL) Pyridine (0.036 mL) and ethyl chloroformate (0.021 mL) were stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/2) to give the title compound (38 mg).
使用對應的原料物質,依與實施例418相同的方法,得到表106記載之實施例419的化合物。The compound of Example 419 shown in Table 106 was obtained by the same method as Example 418 using the corresponding material.
使用對應的原料物質,依與實施例233相同的方法,得到表106~107記載之實施例420~426的化合物。Using the corresponding starting materials, the compounds of Examples 420 to 426 shown in Tables 106 to 107 were obtained in the same manner as in Example 233.
使用對應的原料物質,依與實施例396相同的方法,得到表107記載之實施例427的化合物。The compound of Example 427 shown in Table 107 was obtained by the same method as Example 396, using the corresponding material.
使用對應的原料物質,依與實施例233相同的方法,得到表107記載之實施例428的化合物。The compound of Example 428 shown in Table 107 was obtained by the same method as Example 233 using the corresponding material.
將上述參考例化合物1~346之化學構造及1 H-NMR數據示於表1~46,將上述實施例化合物1~428之化學構造及1 H-NMR數據示於表47~107。The compound of Reference Example 1 to 346 of the chemical structure and 1 H-NMR data are shown in Tables 1 to 46, the above-mentioned compound of Example 428 ~ 1 of chemical structure and 1 H-NMR data are shown in Tables 47 ~ 107.
表中之簡寫中,Ref No.為參考例號碼,Ex No.為實施例號碼,Strc為化學構造式,Solv為1 H-NMR測定溶媒。In the abbreviations in the table, Ref No. is a reference example number, Ex No. is an example number, Strc is a chemical structural formula, and Solv is a 1 H-NMR measurement solvent.
1)人體GnRH受體1(GnRHR1)之選殖及於表現載體的重組以來自人體腦下垂體之cDNA(Bection Dikinson公司)作為模板(templete),將由Kakar等人所報告之人體GnRHR1(Accession No.L03380)之45號至1115號的鹼基排列藉由PCR法進行放大,並插入至pcDNA3.1(+)(Invitrogen公司)之多重選殖部位。所插入之DNA的鹼基序列係與所報告之鹼基序列完全一致。1) Selection of human GnRH receptor 1 (GnRHR1) and recombination of expression vector The cDNA from human pituitary gland (Bection Dikinson) was used as a template (templete), and human GnRHR1 (Accession No) reported by Kakar et al. The base arrangement of No. 45 to No. 1115 of .L03380) was amplified by a PCR method and inserted into a multiple selection site of pcDNA3.1 (+) (Invitrogen). The base sequence of the inserted DNA is identical to the reported base sequence.
2)人體GnRH受體1表現HEK293(人體胎兒腎臟)細胞之調製於經培養(培養基:MEM,10%FCS,含有抗生素,含有非必需胺基酸,含有丙酮酸)之HEK293細胞中,使用Lipofectamine2000(Invitrogen公司),依微脂粒感染法(lipofection)導入經導入了人體GnRHR1基因之表現載體。於導入後培養2天再用於實驗。2) Human GnRH receptor 1 is expressed in HEK293 (human fetal kidney) cells. It is prepared in HEK293 cells cultured (medium: MEM, 10% FCS, containing antibiotics, containing non-essential amino acids, containing pyruvate), using Lipofectamine 2000. (Invitrogen), a expression vector into which a human GnRHR1 gene was introduced was introduced by lipofection. After the introduction, the culture was carried out for 2 days and then used for the experiment.
3)GnRH拮抗效果之測定對於人體GnRHR1之化合物的拮抗作用,係藉由GnRH刺激而造成之細胞內鈣濃度變化進行評價。過渡性地表現GnRHR1之HEK293細胞係去除培養基,將每一孔以200 μ L之洗淨用緩衝液(Hanks’ Balanced Salt Solutions,20mM N-2-羥基乙基哌-N’-2-乙磺酸,1.3mM氯化鈣,0.5mM氯化鎂,0.4mM硫酸鎂)洗淨1次。添加反應於鈣離子之色素溶液(FLIPR Calcium Assay Kit,Molecular Devices公司製)100 μ L,於5%CO2 、37℃下,培養1小時。其後,細胞內鈣濃度係使用FLEX STATION(Molecular Devices公司製)依以下條件進行測定。於加溫至37℃之庫內添加以測定用緩衝液(含0.1%小牛血清白蛋白之洗淨用緩衝液)稀釋之被檢測物質50 μ L,其1分鐘後添加5nM之GnRH50 μ L。使以GnRH刺激所造成之細胞內鈣變動抑制50%的濃度(IC5 0 值),係藉由統計圖(logit plot)算出(表108)。3) Measurement of GnRH antagonistic effect The antagonism of the compound of human GnRHR1 was evaluated by the change of intracellular calcium concentration by GnRH stimulation. The culture medium of the HEK293 cell line transiently expressing GnRHR1 was washed with 200 μL of each buffer (Hanks' Balanced Salt Solutions, 20 mM N-2-hydroxyethylperidine). -N'-2-ethanesulfonic acid, 1.3 mM calcium chloride, 0.5 mM magnesium chloride, 0.4 mM magnesium sulfate) was washed once. 100 μL of a calcium ion-containing pigment solution (FLIPR Calcium Assay Kit, manufactured by Molecular Devices Co., Ltd.) was added thereto, and the mixture was cultured at 5% CO 2 at 37 ° C for 1 hour. Thereafter, the intracellular calcium concentration was measured using FLEX STATION (manufactured by Molecular Devices Co., Ltd.) under the following conditions. Add 50 μL of the test substance diluted with buffer (washing buffer containing 0.1% calf serum albumin) to a chamber warmed to 37 ° C, and add 5 nM of GnRH 50 μ L after 1 minute. . So that intracellular calcium changes caused by GnRH stimulation of inhibitory concentration (IC 5 0 value) of 50%, based by the chart (logit plot) was calculated (Table 108).
1)尾靜脈內投予之藥物濃度測定用檢體之製作使用經斷食一晚之SD系小鼠作為實驗動物(CHARLES RIVER,雄性7周齡,170-210g)。對試驗化合物1mg,依N,N-二甲基乙醯胺0.2mL、生理食鹽水0.798mL、及2N之NaOH 0.002mL的比例進行添加而使其溶解,調製1.0mg/mL溶液。測定小鼠體重,將試驗化合物依1mL/kg之用量(1mg/kg)於無麻醉下進行尾靜脈內投予。尾靜脈內投予係使用26G注射針及1mL之注射器(syringe)所進行。採血時間設為尾靜脈內投予後2、15、60、120、240及360分鐘。將血液進行離心,而將血漿作為血中藥物濃度測定用檢體。1) Preparation of drug concentration measurement for tail vein administration SD mice that had been fasted for one night were used as experimental animals (CHARLES RIVER, male 7-week old, 170-210 g). 1 mg of the test compound was added in a ratio of 0.2 mL of N,N-dimethylacetamide, 0.798 mL of physiological saline, and 0.002 mL of 2N NaOH to prepare a 1.0 mg/mL solution. The body weight of the mice was measured, and the test compound was administered to the tail vein intravenously at an amount of 1 mL/kg (1 mg/kg) without anesthesia. The tail vein administration was carried out using a 26G injection needle and a 1 mL syringe. The blood collection time was set at 2, 15, 60, 120, 240, and 360 minutes after administration in the tail vein. The blood is centrifuged, and the plasma is used as a blood drug concentration measurement sample.
2)經口投予之藥物濃度測定用檢體之製作使用經斷食一晚之SD系小鼠作為實驗動物(CHARLES RIVER,雄性7周齡,170-210g)。對試驗化合物3mg,依N,N-二甲基乙醯胺0.2mL、0.5%甲基纖維素鈉水溶液9.794mL、及2N之NaOH 0.006mL的比例進行添加而使其溶解,調製0.3mg/mL溶液。測定小鼠體重,將試驗化合物依10mL/kg之用量(3mg/kg)進行經口投予。經口投予係使用鼠用投藥器(sonde)及2.5mL之注射器(syringe)所進行。採血時間設為尾靜脈內投予後15、30、60、120、240及360分鐘。將血液進行離心,而將血漿作為血中藥物濃度測定用檢體。2) Preparation of drug concentration for oral administration The SD mice that had been fasted for one night were used as experimental animals (CHARLES RIVER, male 7-week old, 170-210 g). 3 mg of the test compound was added in a ratio of 0.2 mL of N,N-dimethylacetamide, 9.794 mL of 0.5% methylcellulose sodium solution, and 0.006 mL of 2N NaOH to prepare a solution of 0.3 mg/mL. Solution. The body weight of the mice was measured, and the test compound was orally administered at a dose of 10 mL/kg (3 mg/kg). Oral administration was carried out using a mouse doser (sonde) and a 2.5 mL syringe (syringe). The blood collection time was set at 15, 30, 60, 120, 240 and 360 minutes after administration in the tail vein. The blood is centrifuged, and the plasma is used as a blood drug concentration measurement sample.
3)藥物濃度之測定於藉上述1)及2)所得之血漿0.025mL中,依常法添加適當之內部標準物質0.1mL後,加入乙腈0.875mL,進行去蛋白質。於離心後,將其上清液0.005mL注入至LC-MS/MS中。血中藥物濃度係藉LC-MS/MS依以下條件進行測定。尚且,檢測線係於空白(blank)血漿0.05mL中依常法適當添加內部標準物質及各種測定對象化合物,並藉與上述相同之操作予以製成。3) Measurement of drug concentration In 0.025 mL of the plasma obtained by the above 1) and 2), 0.1 mL of an appropriate internal standard substance was added according to a usual method, and then 0.875 mL of acetonitrile was added to carry out deproteinization. After centrifugation, 0.005 mL of the supernatant was injected into LC-MS/MS. The blood drug concentration was determined by LC-MS/MS under the following conditions. Further, the detection line was added to 0.05 mL of blank plasma in an appropriate manner by appropriately adding an internal standard substance and various measurement target compounds, and the same procedure as above was carried out.
(LC)裝置:Agilent1100管柱:Cadenza C18 3 μ m 4.6×50mm移動相:10mM醋酸銨水溶液(pH4.5)(A)/乙腈(B)(時間及(A)、(B)之比例係示於表109。)管柱溫度:40℃流速:0.5mL/min(LC) device: Agilent 1100 column: Cadenza C18 3 μ m 4.6 × 50 mm mobile phase: 10 mM aqueous ammonium acetate solution (pH 4.5) (A) / acetonitrile (B) (time and ratio of (A), (B) Shown in Table 109.) Column temperature: 40 ° C Flow rate: 0.5 mL / min
(MS/MS)裝置:API-4000離子化法:ESI(Turbo Ion Spray)(MS/MS) device: API-4000 ionization method: ESI (Turbo Ion Spray)
尚且,生體利用率(%)係藉由依上述方法所得之各時間的血中藥物濃度,使用PharsightCorporation公司製WinNonlin Professional,求得試驗化合物之尾靜脈內投予及經口投予的血中藥物濃度-時間曲線下面積,並根據下式算出。Further, the bioavailability (%) is obtained by administering the blood concentration of the drug at each time obtained by the above method, using WinNonlin Professional manufactured by Pharsight Corporation, to obtain the tail vein intravenous administration and oral administration of the test compound. The area under the concentration-time curve is calculated according to the following formula.
生體利用率(%)={[(經口投予時之血中藥物濃度-時間曲線下面積)/3]/(尾靜脈內投予時之血中藥物濃度-時間曲線下面積)}×100Bioavailability (%) = { [(area in the blood concentration-time curve when administered orally) / 3] / (area in the blood concentration in the tail vein - the area under the time curve)} ×100
將經口投予時之最高血中藥物濃度(Cmax)、生體利用率、投予360分鐘後之血中藥物濃度(C3 6 0 )分別示於表110~112。The maximum blood when administered orally in the concentration of the drug (a Cmax), bioavailability, 360 minutes after administration of blood drug concentration (C 3 6 0) are shown in Tables 110 to 112.
表110~112中,對照化合物1係上述專利文獻2記載之實施例6(4)之磺醯胺化合物,對照化合物2係上述專利文獻2記載之實施例31之磺醯胺化合物。In Tables 110 to 112, the control compound 1 is the sulfonamide compound of Example 6 (4) described in Patent Document 2, and the control compound 2 is the sulfonamide compound of Example 31 described in Patent Document 2.
由以上結果,相較於對照化合物,本發明之縮合雜環衍生物係經口投予之血中動態(血中移行性、持續性)較優良。例如,實施例48、146、191、202、233、367、414、420之縮合雜環衍生物,係相較於實施例22之具有磺醯胺基之化合物、實施例95之具有醯胺基之化合物,於血中移行性方面更優良,而更適合作為經口投予用的醫藥組成物。又,實施例146、202、233、271、367、414、420之縮合雜環衍生物(更佳為實施例146、233、271、367、414),係相較於對照化合物,可維持經口投予後6小時的血中藥物濃度,而可更適合作為持續性優良的醫藥組成物。From the above results, the condensed heterocyclic derivative of the present invention is superior in blood dynamics (transition in blood, persistence) by oral administration as compared with the control compound. For example, the condensed heterocyclic derivatives of Examples 48, 146, 191, 202, 233, 367, 414, 420 are compared to the compound having a sulfonamide group of Example 22, and the amidino group of Example 95. The compound is more excellent in migration in blood, and is more suitable as a pharmaceutical composition for oral administration. Further, the condensed heterocyclic derivatives of Examples 146, 202, 233, 271, 367, 414, and 420 (more preferably, Examples 146, 233, 271, 367, and 414) are maintained as compared with the control compound. The concentration of blood in the blood 6 hours after oral administration is more suitable as a pharmaceutical composition with excellent persistence.
本發明之縮合雜環衍生物(I)或其前驅藥或其藥理學上所容許之鹽、或其之水合物或溶媒合物,由於具有優越的GnRH拮抗作用,故可調節性腺刺激荷爾蒙釋出荷爾蒙的作用,控制性腺刺激荷爾蒙及性荷爾蒙的產生、分泌,藉此而使用作為性荷爾蒙依存性疾病的預防或治療劑。因此,藉由本發明,可提供前列腺肥大症、子宮肌瘤、子宮內膜症、子宮纖維腫瘤、青春期早發症、無月經症、月經前症候群、月經困難症、多囊胞性卵巢症候群、紅斑性狼瘡、多毛症、侏儒症、睡眠障礙、青春痘、禿頭症、阿茲海默症、不孕症、過敏性腸症候群、前列腺癌、子宮癌、卵巢癌、乳癌及腦下垂體腫瘤之預防或治療劑、生殖調節劑、避孕藥、排卵誘發劑、或性荷爾蒙依存性癌手術後再發預防劑等。The condensed heterocyclic derivative (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof thereof, can modulate gonadotropin-induced hormone release due to superior GnRH antagonism The role of hormones to control the production and secretion of hormones and sex hormones by the gonads, thereby using as a prophylactic or therapeutic agent for sexual hormone-dependent diseases. Therefore, according to the present invention, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, early onset of adolescence, no menstrual disease, premenstrual syndrome, menstrual difficulties, polycystic ovarian syndrome, and erythema can be provided. Lupus, hirsutism, dwarfism, sleep disorders, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumor prevention or A therapeutic agent, a reproductive regulator, a contraceptive, an ovulation inducing agent, or a prophylactic agent after surgery for sex hormone-dependent cancer.
Claims (28)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005304395 | 2005-10-19 | ||
JP2006147019 | 2006-05-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200732309A TW200732309A (en) | 2007-09-01 |
TWI400074B true TWI400074B (en) | 2013-07-01 |
Family
ID=37962485
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW095138520A TWI400074B (en) | 2005-10-19 | 2006-10-19 | Condensed heterocyclic derivatives, pharmaceutical compositions containing them and their pharmaceutical use |
Country Status (21)
Country | Link |
---|---|
US (1) | US9040693B2 (en) |
EP (1) | EP1939204B3 (en) |
JP (2) | JP4955566B2 (en) |
KR (1) | KR101384132B1 (en) |
AU (1) | AU2006305271B2 (en) |
BR (1) | BRPI0617436B8 (en) |
CA (1) | CA2624492C (en) |
CY (1) | CY1113898T1 (en) |
DK (1) | DK1939204T6 (en) |
ES (1) | ES2398917T7 (en) |
HK (1) | HK1125110A1 (en) |
IL (1) | IL190754A (en) |
NL (1) | NL301202I2 (en) |
NO (1) | NO343185B1 (en) |
NZ (1) | NZ567300A (en) |
PL (1) | PL1939204T6 (en) |
PT (1) | PT1939204E (en) |
RU (1) | RU2418803C2 (en) |
SI (1) | SI1939204T1 (en) |
TW (1) | TWI400074B (en) |
WO (1) | WO2007046392A1 (en) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8263588B2 (en) | 2007-04-06 | 2012-09-11 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
AR065948A1 (en) * | 2007-04-06 | 2009-07-15 | Neurocrine Biosciences Inc | GONADOTROPINE LIBERATING HORMONE RECEIVER ANTAGONISTS AND PROCEDURES RELATED TO THEMSELVES |
CA2682400A1 (en) * | 2007-04-18 | 2008-11-06 | Kissei Pharmaceutical Co., Ltd. | Fused heterocyclic derivative, pharmaceutical composition comprising the derivative, and use of the composition for medical purposes |
CA2682519A1 (en) * | 2007-04-18 | 2008-11-06 | Kissei Pharmaceutical Co., Ltd. | Fused heterocyclic derivative, pharmaceutical composition comprising the derivative, and use of the composition for medical purposes |
SG183243A1 (en) | 2010-02-10 | 2012-09-27 | Kissei Pharmaceutical | Salt of fused heterocyclic derivative and crystal thereof |
CN104755465A (en) * | 2012-08-24 | 2015-07-01 | 武田药品工业株式会社 | Heterocycic compound |
WO2014042176A1 (en) * | 2012-09-14 | 2014-03-20 | キッセイ薬品工業株式会社 | Method for producing fused-heterocyclic derivative, and production intermediate thereof |
JP6574444B2 (en) * | 2014-01-06 | 2019-09-11 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Carbocyclic sulfone RORγ regulator |
JP6987060B2 (en) | 2016-08-08 | 2021-12-22 | キッセイ薬品工業株式会社 | Dosage and administration of endometriosis therapeutic agent |
KR20190110567A (en) * | 2017-01-31 | 2019-09-30 | 베루 인코퍼레이티드 | Compositions and methods for long-term release of gonadotropin-releasing hormone (GnRH) antagonists |
SG11201911598WA (en) | 2017-06-05 | 2020-01-30 | ObsEva SA | Gonadotropin-releasing hormone antagonist dosing regimens for the treatment of endometriosis |
CA3066188A1 (en) | 2017-06-05 | 2018-12-13 | ObsEva S.A. | Gonadotropin-releasing hormone antagonist dosing regimens for treating uterine fibroids and reducing menstrual blood loss |
UA127488C2 (en) * | 2018-01-30 | 2023-09-06 | Інсайт Корпорейшн | Processes for preparing (1 -(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidine-4-one) |
US20220117969A1 (en) | 2018-10-29 | 2022-04-21 | ObsEva S.A. | Compositions and methods for the treatment of adenomyosis and rectovaginal endometriosis |
US20230067378A1 (en) | 2018-11-07 | 2023-03-02 | ObsEva S.A. | Compositions and methods for the treatment of estrogen-dependent disorders |
JP2022543308A (en) | 2019-08-08 | 2022-10-11 | オブセヴァ エス.エー. | Compositions and methods for the treatment of estrogen dependent disorders |
CA3150089A1 (en) | 2019-08-08 | 2021-02-11 | ObsEva S.A. | Gnrh antagonists for the treatment of estrogen-dependent disorders |
US20240158413A1 (en) * | 2021-02-23 | 2024-05-16 | Soter Biopharma Pte. Ltd. | Fused polycyclic substituted 5-carboxylic acid thienopyrimidine dione compound and use thereof |
CN116940575A (en) * | 2021-02-23 | 2023-10-24 | 深圳市康哲药业有限公司 | Thienopyrimidinedione compounds and application thereof |
AU2023215938A1 (en) | 2022-02-04 | 2024-08-22 | Kissei Pharmaceutical Co., Ltd. | Oral solid preparation |
WO2024037532A1 (en) * | 2022-08-16 | 2024-02-22 | 深圳市康哲生物科技有限公司 | Salt type and crystal form of thienopyrimidinone derivative |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6015789A (en) * | 1996-04-30 | 2000-01-18 | Takeda Chemical Industries, Ltd. | Combined use of GnRH agonist and antagonist |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69622677T2 (en) * | 1995-12-08 | 2003-03-20 | Takeda Chemical Industries, Ltd. | Inhibitors of prolactin synthesis |
CA2254769A1 (en) | 1996-05-20 | 1997-11-27 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
GB0124627D0 (en) * | 2001-10-15 | 2001-12-05 | Smithkline Beecham Plc | Novel compounds |
CA2545725A1 (en) | 2003-11-14 | 2005-06-02 | Merck Sharp & Dohme Limited | Bicyclic pyrimidin-4-(3h)-ones and analogues and derivatives thereof which modulate the function of the vanilloid-1 receptor (vr1) |
AU2004303876A1 (en) * | 2003-12-19 | 2005-07-07 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
EP1847541A4 (en) | 2005-02-03 | 2009-12-30 | Takeda Pharmaceutical | Fused pyrimidine derivative and uses thereof |
-
2006
- 2006-10-17 RU RU2008119462/04A patent/RU2418803C2/en active
- 2006-10-17 ES ES06811925T patent/ES2398917T7/en active Active
- 2006-10-17 SI SI200631557T patent/SI1939204T1/en unknown
- 2006-10-17 JP JP2007540993A patent/JP4955566B2/en active Active
- 2006-10-17 DK DK06811925.4T patent/DK1939204T6/en active
- 2006-10-17 BR BRPI0617436A patent/BRPI0617436B8/en active IP Right Grant
- 2006-10-17 PT PT68119254T patent/PT1939204E/en unknown
- 2006-10-17 CA CA2624492A patent/CA2624492C/en active Active
- 2006-10-17 WO PCT/JP2006/320681 patent/WO2007046392A1/en active Application Filing
- 2006-10-17 US US12/089,674 patent/US9040693B2/en active Active
- 2006-10-17 PL PL06811925.4T patent/PL1939204T6/en unknown
- 2006-10-17 AU AU2006305271A patent/AU2006305271B2/en active Active
- 2006-10-17 KR KR1020087010997A patent/KR101384132B1/en active IP Right Grant
- 2006-10-17 NZ NZ567300A patent/NZ567300A/en unknown
- 2006-10-17 EP EP06811925.4A patent/EP1939204B3/en active Active
- 2006-10-19 TW TW095138520A patent/TWI400074B/en active
-
2008
- 2008-04-09 IL IL190754A patent/IL190754A/en active IP Right Grant
- 2008-05-19 NO NO20082249A patent/NO343185B1/en unknown
-
2009
- 2009-04-09 HK HK09103380.3A patent/HK1125110A1/en unknown
-
2012
- 2012-01-19 JP JP2012008680A patent/JP5319797B2/en active Active
-
2013
- 2013-04-02 CY CY20131100276T patent/CY1113898T1/en unknown
-
2022
- 2022-11-01 NL NL301202C patent/NL301202I2/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6015789A (en) * | 1996-04-30 | 2000-01-18 | Takeda Chemical Industries, Ltd. | Combined use of GnRH agonist and antagonist |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI400074B (en) | Condensed heterocyclic derivatives, pharmaceutical compositions containing them and their pharmaceutical use | |
JP5313883B2 (en) | Nitrogen-containing fused ring derivative, pharmaceutical composition containing the same, and pharmaceutical use thereof | |
JP3789538B2 (en) | Thienopyrimidine derivatives, their production and use | |
HUT76320A (en) | Bicyclic thiophene derivatives, process for preparation thereof and pharmaceutical compositions containing them | |
JP5352450B2 (en) | Fused heterocyclic derivative, pharmaceutical composition containing the same, and pharmaceutical use thereof | |
JP5352449B2 (en) | Fused heterocyclic derivative, pharmaceutical composition containing the same, and pharmaceutical use thereof | |
JP5308342B2 (en) | Nitrogen-containing fused ring derivative, pharmaceutical composition containing it, and pharmaceutical use thereof | |
JPH08295693A (en) | Condensed thiophene derivative, its production and use thereof | |
WO2022067566A1 (en) | Pyrimidinedione compound containing saturated oxygen-containing heterocyclic group and use thereof | |
TW201518304A (en) | Spiroindoline derivatives and pharmaceutical compositions thereof | |
WO2022067573A1 (en) | Sulfonamide-substituted heteroaryl pyrimidinedione compound and use thereof | |
JPH0948777A (en) | Diazepinone compounds, their production and therapeutic agent |